JP5597353B2 - Substituted pyrazole compounds - Google Patents

Description

(Cross-reference of related applications)
This application includes US provisional application 60 / 722,217, filed September 30, 2005, US provisional application 60 / 732,340, filed October 31, 2005, and US provisional application, filed November 4, 2005. Claims 60 / 733,868, all of which are incorporated herein by reference in their entirety.

(Technical field of the present invention)
The present invention is directed to protein kinase inhibitors, compositions comprising such inhibitors, and methods of use thereof. More particularly, the present invention relates to inhibitors of Aurora A (Aurora-2) protein kinase. The present invention also relates to pharmaceutical compositions and methods for treating diseases related to protein kinases, particularly diseases related to Aurora A such as cancer.

(Background of the Invention)
Research on new therapeutic agents has been greatly helped in recent years by a better understanding of the structure of enzymes and other biomolecules associated with target diseases. One important class of enzymes that has been the subject of extensive research is protein kinases.

Protein kinases mediate intracellular signaling by producing a phosphotransfer reaction from a nucleoside triphosphate to a protein receptor involved in the signal pathway. There are many kinases and pathways through which extracellular and other stimuli produce various cellular responses within the cell. Examples of such stimuli include environmental and chemical stress signals (eg, osmotic shock, heat shock, ultraviolet light, bacterial endotoxin, H ₂ O ₂ ), cytokines (eg, interleukin-1 (IL- 1) and tumor necrosis factor α (TNF-α)), and growth factors such as granulocyte macrophage colony stimulating factor (GM-CSF) and fibroblast growth factor (FGF)). Extracellular stimulation results in one or more cellular responses related to cell proliferation, migration, differentiation, hormone secretion, transcription factor activation, muscle contraction, glucose metabolism, regulation of protein synthesis, and regulation of the cell cycle. obtain.

  Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, or hormone related diseases. Accordingly, considerable efforts have been made in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.

  In humans, there are three highly related Aurora kinases, all serine / threonine protein kinases (Andrews, PD et al., Curr. Opin. Cell. Biol. 2003, 15, 672-683; Carmena, M., Earnshow, WC, Nat.Rev.Mol.Cell.Biol.2003, 4, 842-854; Brown, JR, et al., BMC Evol.Biol.2004, 4, 39; , D., Oncogene 2005, 24, 5005-5015). Despite the sequence relationships of Aurora A, B and C, the localization and function of these kinases are very different. Consequently, overexpression or activation of each of these kinases can be associated with various disease states including proliferative diseases such as cancer.

  Members of the family show different subcellular localization during mitosis and are degraded by proteosomes after the end of mitosis (Graham et al. (2002) J. Biol. Chem. 277: 42419-22). Kinases are often found in complex with other proteins, including cytoskeletal structures.

  Aurora kinases share a conserved C-terminal catalytic domain, with larger changes being observed at the N-terminus. Aurora A (Aurora-2) is unique in that there are two lysine residues in the nucleotide binding domain of the kinase (Warner et al. (2003) Molecular Cancer Therapeutics 2: 589-95).

Maximum levels of Aurora A polypeptide and maximum Aurora A activity are observed in the G ₂ / M transition leading to pre-mitosis, and the polypeptide is localized at the spindle pole (Graham et al. (2002) J Biol.Chem.277: 42419-22; Sakai et al. (2002) J.Biol.Chem.277: 48714-23). Aurora A is thought to regulate chromosome replication with aberrant expression associated with aneuploidy and malignant clinical phenotypes, particularly in solid tumors. Such observations, and further experimental data, suggest that Aurora A disrupts the signaling cascade that regulates chromosome segregation (Sen et al. (2002) J. Nat. Cancer. Inst. 94: 1320. -29).

  Aurora A is also thought to function in mitosis, possibly in homologous chromosome segregation and spindle rotation. Injection of antibodies against Aurora A into Xenopus oocytes prevents first polar body release and causes meiosis I arrest (Castro et al. (2003) J. Biol. Chem. 2236-41). The Xenopus kinesin-like protein, Eg5, is known to be a substrate for Aurora-2 (Castro et al. (2003) J. Biol. Chem. 2236-41).

  In addition, in vitro studies have shown that Aurora A is incorporated into chromatin and phosphorylates histone H3, and possibly histone H2B (Scrittori et al. (2001) J. Biol. Chem. 276: 30002-10). H3 phosphorylation, for example at serine-10, in the chromosome assembly is thought to be a protective event in eukaryotic cell division. Inhibition of the H3 phosphorylation results in chromosomal condensation, abnormal segregation, and chromosomal loss during mitosis and meiosis (Scrittori et al. (2001) J. Biol. Chem. 276: 30002-10).

  Thus, a new model for histone phosphorylation is similar to that of histone acetylation, where partially overlapping enzyme activities are related to histone modification, but different enzymes are under different cellular conditions. Can function. For example, some enzymes can modify histones in large quantities, while other enzymes target, ie, sequence-specific or domain-specifically modify histones in the context of assembled chromatin (eg, Scrittori et al., (2001) J. Biol. Chem. 276: 30002-10). According to this model, Aurora A appears to be a kinase involved in targeted histone modifications in the context of assembled or assembling chromatin.

  Other members of the Aurora kinase family are also associated with mitosis and meiosis. Like Aurora A, Aurora B is involved in different protein phosphorylation events that regulate the cell cycle. Unlike Aurora A, Aurora B is localized to chromatin in the centromere from the early to late metaphase transition, relocalized to microtubules in the midspindle zone during the end, and then centrosomes during cytokinesis (See Andrews, PD, Oncogene 2005, 24, 5005-5015). The function of Aurora B is to ensure correct chromosome segregation and proper cytokinesis. Aurora B is thought to be related to survivin, a polypeptide that is associated with intracellular centromeres and undergoes a considerable extension during mitosis. Survivin is thought to be involved in inhibiting apoptosis and controlling the cell cycle. Interestingly, both Aurora B and survivin are delocalized during the nuclear mitosis of megakaryocytes, a process that eliminates late anaphase and cytokinesis, resulting in ploidy of megakaryocytes. (Zhang et al. (2004) Blood 103: 3717-26). Inhibition of this function in proliferative diseases such as cancer results in hemostasis and cell death, making such inhibitors useful in cancer chemotherapy.

  Aurora C (Aurora-3) is the least studied member of the family. Aurora C is localized to the centrosome from late to late (or even in cytokinesis) and is highly expressed in the testis (Brown et al. (2004) BMC Evolutionary Biology 4:39).

  As described above, Aurora kinase is overexpressed in certain types of cancer, including colon cancer, breast cancer, and other solid carcinomas. While genes encoding Aurora B kinase and Aurora A kinase tend to be amplified in certain types of cancer, genes encoding Aurora C kinase are present in regions of the chromosome that are susceptible to rearrangements and deletions. . Aurora A is associated with a variety of malignancies, including primary colon cancer, colorectal cancer, breast cancer, stomach cancer, ovarian cancer, prostate cancer, and cervical cancer, neuroblastoma, and other solid carcinomas (Warner) (2003) Molecular Cancer Therapeutics 2: 589-95).

  Inhibitors of Aurora A have been described. For example, Harrington et al. ((2004) Nat. Med. 10: 262-67), VX-680, is a small molecule inhibitor that prevents cell cycle progression and induces apoptosis in certain types of tumors in an in vivo xenograft model. Is described. Pyrazole Aurora A kinase inhibitors are also described in US Pat. No. 6,653,301 (Bebbington et al., Issued November 25, 2003).

  Hauf et al. ((2003) J. Cell. Biol. 161: 281-294), both sisters bound to a single spindle pole, causing cells to migrate to a late stage with unidirectionally oriented chromosomes. Indolinone (hesperazine) was identified as an inhibitor of Aurora B with a centromere (a state known as synthetic binding).

  Ditchfield et al. ((2003) J. Cell. Biol. 161: 267-280), ZM447439 ((4- (4- (N-benzoylamino)), an Aurora kinase inhibitor that prevents chromosome alignment, segregation, and cytokinesis. Anilino) -6-methoxy-7- (3- (1-morpholino) propoxy) quinazoline) was described.

  Thus, kinase inhibitors, particularly inhibitors of Aurora kinases are of particular interest in the treatment of certain diseases including cancer. Compounds that exhibit such inhibition are valuable.

(Summary of Invention)
The present invention provides compounds or pharmaceutically acceptable derivatives or prodrugs, compositions and methods for the treatment of diseases mediated by kinases. Such diseases include melanoma, lymphoma, leukemia, colon cancer, colorectal cancer, breast cancer, lung cancer, kidney cancer, pancreatic cancer, renal cancer, central nervous system cancer, stomach cancer, ovarian cancer, Primary cancers such as prostate cancer, cervical cancer, and neuroblastoma, secondary cancers, and metastatic cancers are included.

These compounds have the general formula I:

Or a pharmaceutically acceptable derivative or prodrug thereof [wherein
R ^x and R ^y are independently selected from the group consisting of —T—R ³ and —L—Z—R ³ ;
Q ′ is −CR ⁶ ″ = CR ⁶ ″ − and

Is selected from the group consisting of, wherein said -CR 6 ^"= CR 6" ^- may be a cis or trans double bonds or mixtures thereof;
R ¹ is -T- (Ring D);
Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from the group consisting of aryl, heteroaryl, heterocyclyl, and carbocyclyl, and the heteroaryl or heterocyclyl ring includes nitrogen, oxygen, and having from 1 to 4 ring heteroatoms selected from the group consisting of sulfur, wherein each substitutable ring carbon of ring D is oxo, -T-R 5 or ^-V-Z-, Independently substituted by R ⁵ and each substitutable ring nitrogen of ring D is independently substituted by R ⁴ ;
T is a valence bond or — (C (R ^{6 ′} ) ₂ ) —A—;
A is a valence bond or _C 1 -C ₃ alkylidene chain, wherein said _C 1 -C ₃ methylene units of the alkylidene chain, -O -, - S -, - N (R 4) -, - _{CO -, - CONH -, -} NHCO -, - SO 2 -, - SO 2 NH -, - NHSO 2 -, - CO 2 -, - OC (O) -, - OC (O) NH-, or -NHCO ₂ - which is optionally substituted by;
Z is a C _1-4 alkylidene chain;
L _{is, -O -, - S -,} - SO -, - SO 2 -, - N (R 6) SO 2 -, - SO 2 N (R 6) -, - N (R 6) -, - CO _{^{-, - CO 2 -, -}} N (R 6) CO -, - N (R 6) C (O) O -, - N (R 6) CON (R 6) -, - N (R 6) SO 2 ^{N (R 6) -, -} N (R 6) N (R 6) -, - CON (R 6) -, - OC (O) N (R 6) -, - C (R 6) 2 O-, _{^{-C (R 6) 2 -,}} - C (R 6) 2 SO -, - C (R 6) 2 SO 2 -, - C (R 6) 2 SO 2 N (R 6) -, - C (R _{^{6) 2 N (R 6)}} -, - C (R 6) 2 N (R 6) C (O) -, - C (R 6) 2 N (R 6) C (O) O -, - C ( ^{R 6) = NN (R 6} ) -, - C (R 6) = N-O -, - C (R 6) 2 N (R 6) _{^{(R 6) -, - C}} (R 6) 2 N (R 6) SO 2 N (R 6) -, and _{^{-C (R 6) 2 N (}} R 6) CON (R 6) - from the group consisting of Selected;
R ² and R ^{2 ′} are independently selected from the group consisting of —R and —T—W—R ⁶ , or R ² and R ^{2 ′} together with the atoms between them, nitrogen, oxygen And forms a fused, 5- to 8-membered, unsaturated or partially unsaturated ring having 0 to 3 ring heteroatoms selected from the group consisting of sulfur and R ² and R ^{2 ′} Each substitutable ring carbon of the fused ring formed by is independently substituted by halo, oxo, —CN, —NO ₂ , R ⁷ , or —V—R ⁶ , and R ² and R ² Each substitutable ring nitrogen of said ring formed by ^' is independently substituted by -R ⁴ ;
R ³ is —R, —halo, —OR, —C (═O) R, —CO ₂ R, —COCOR, —COCH ₂ COR, —NO ₂ , —CN, —S (O) R, —S. (O) ₂ R, —SR, —N (R ⁴ ) ₂ , —CON (R ⁷ ) ₂ , —SO ₂ N (R ⁷ ) ₂ , —OC (═O) R, —N (R ⁷ ) COR _{^{, -N (R 7) CO 2}} (C 1~6 _{^{aliphatic), - N (R 4)}} N (R 4) 2, -C = NN (R 4) 2, -C = N-OR, -N ^{(R 7)} consisting of _{^{CON (R 7) 2, -N}} (R 7) SO 2 N (R 7) 2, -N (R 4) SO 2 R, and -OC (= O) N (R ) 2 Selected from the group;
Each R is independently from hydrogen or C _1-6 aliphatic, C _6-10 aryl, a heteroaryl ring having 5-10 ring atoms, and a heterocyclyl ring having 5-10 ring atoms. An optionally substituted group selected from the group consisting of;
Each R ⁴ is independent of the group consisting of —R ⁷ , —COR ⁷ , —CO ₂ (optionally substituted C _1-6 aliphatic), —CON (R ⁷ ) ₂ , and —SO ₂ R ^7. Is selected;
Each R ⁵ is —R, halo, —OR, —C (═O) R, —CO ₂ R, —COCOR, —NO ₂ , —CN, —S (O) R, —SO ₂ R, — SR, —N (R ⁴ ) ₂ , —CON (R ⁴ ) ₂ , —SO ₂ N (R ⁴ ) ₂ , —OC (═O) R, —N (R ⁴ ) COR, —N (R ⁴ ) CO _{2 (C 1 to 6} aliphatic optionally _{^{substituted), - N (R 4)}} N (R 4) 2, -C = NN (R 4) 2, -C = N-OR, -N (R ⁴ ) CON (R ⁴ ) ₂ , —N (R ⁴ ) SO ₂ N (R ⁴ ) ₂ , —N (R ⁴ ) SO ₂ R, and —OC (═O) N (R ⁴ ) ₂ Independently selected from;
V _{is, -O -, - S -,} - SO -, - SO 2 -, - N (R 6) SO 2 -, - SO 2 N (R 6) -, - N (R 6) -, - CO _{^{-, - CO 2 -, -}} N (R 6) CO -, - N (R 6) C (O) O -, - N (R 6) CON (R 6) -, - N (R 6) SO 2 N (R ⁶ ) —, —N (R ⁶ ) N (R ⁶ ) —, —C (O) N (R ⁶ ) —, —OC (O) N (R ⁶ ) —, —C (R ⁶ ) ₂ O—, —C (R ⁶ ) ₂ S—, —C (R ⁶ ) ₂ SO—, —C (R ⁶ ) ₂ SO ₂ —, —C (R ⁶ ) ₂ SO ₂ N (R ⁶ ) — _{^{, -C (R 6) 2 N}} (R 6) -, - C (R 6) 2 N (R 6) C (O) -, - C (R 6) 2 N (R 6) C (O) O ^{-, - C (R 6)} = NN (R 6) -, - C (R 6) = N-O -, - C (R 6) 2 N (R _{^{6) N (R 6) -}} , - C (R 6) 2 N (R 6) SO 2 N (R 6) -, and _{^{-C (R 6) 2 N (}} R 6) CON (R 6) - from Selected from the group consisting of:
W represents —C (R ⁶ ) ₂ O—, —C (R ⁶ ) ₂ S—, —C (R ⁶ ) ₂ SO—, —C (R ⁶ ) ₂ SO ₂ —, —C (R ⁶ ). _{^{2 SO 2 N (R 6)}} -, - C (R 6) 2 N (R 6) -, - CO -, - CO 2 -, - C (R 6) OC (O) -, - C (R 6 _{^{) OC (O) N (R}} 6) -, - C (R 6) 2 N (R 6) CO -, - C (R 6) 2 N (R 6) C (O) O -, - C (R ⁶ ) = NN (R ⁶ )-, -C (R ⁶ ) = N-O-, -C (R ⁶ ) ₂ N (R ⁶ ) N (R ⁶ )-, -C (R ⁶ ) ₂ N ( Selected from the group consisting of R ⁶ ) SO ₂ N (R ⁶ ) —, —C (R ⁶ ) ₂ N (R ⁶ ) CON (R ⁶ ) —, and —CON (R ⁶ ) —;
Each R ⁶ is independently selected from the group consisting of hydrogen and optionally substituted C _1-4 aliphatic groups, or two R ⁶ groups on the same nitrogen atom together with the nitrogen atom Can form a 3-6 membered heterocyclyl or heteroaryl ring;
Each R ^{6 ′} is independently selected from the group consisting of hydrogen and C _1-4 aliphatic groups, or two R ^{6 ′} on the same carbon atom are taken together to form a 3-8 membered carbocyclic ring. Forming;
Each R ^{6 ″} is independently selected from the group consisting of hydrogen, C _1-4 aliphatic groups, halogen, optionally substituted aryl, and optionally substituted heteroaryl, or on adjacent carbon atoms Two R ^{6 ″} together form a 5-7 membered carbocycle;
Each R ⁷ is independently selected from the group consisting of hydrogen and optionally substituted C _1-6 aliphatic groups, or two R ⁷ on the same nitrogen together with the nitrogen 5 Forms an 8-membered heterocyclyl or heteroaryl ring].

(Detailed explanation)
As used herein, the following definitions shall apply unless otherwise indicated. The phrase “optionally substituted” is used interchangeably with the phrase “substituted or not substituted” or the term “substituted (not substituted)”. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and each substitution is independent of the other.

The term “acetamido” refers to the group —NHC (═O) CH ₃ .

As used herein, the term “aliphatic” is a straight chain, branched chain, or cyclic that is fully saturated or contains one or more units of unsaturation but is not aromatic. It means C ₁ -C ₁₂ hydrocarbon. For example, suitable aliphatic groups include substituted or unsubstituted linear, branched, or cyclic alkyl, alkenyl, alkynyl groups include. The terms “alkyl”, “alkoxy”, “hydroxyalkyl”, “alkoxyalkyl”, and “alkoxycarbonyl” used alone or as part of a larger moiety include 1 to 12 carbon atoms Both straight and branched chains are included. The terms “alkenyl” and “alkynyl” used alone or as part of a larger moiety are intended to include both straight and branched chains containing 2 to 12 carbon atoms. Alone or in the term "cycloalkyl" used as part of a larger moiety shall include that is completely saturated cyclic C ₃ -C ₁₂ hydrocarbons.

The term “amino” refers to the NH ₂ group.

  The term “alkylamino” refers to an amino group in which one of the hydrogen atoms is replaced by an alkyl group.

  The term “dialkylamino” refers to an amino group in which a hydrogen atom is replaced by an alkyl group, which alkyl groups may be the same or different.

  The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” mean alkyl, alkenyl or alkoxy optionally substituted with one or more halogen atoms.

  The term “halogen” means F, Cl, Br, or I.

The term “heteroatom” means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and any quaternized form of any basic nitrogen. Similarly, the term “nitrogen” includes heterocyclic substitutable nitrogens. By way of example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH ( It may be NR ⁺ (as in pyrrolidinyl) or NR ⁺ (as in N-substituted pyrrolidinyl).

  The term “carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic” as used herein means an aliphatic ring system having 3 to 14 members. The term “carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic”, whether saturated or partially unsaturated, also means an optionally substituted ring. The term “carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic” is fused to one or more aromatic or non-aromatic rings, such as in decahydronaphthyl or tetrahydronaphthyl. Also included are aliphatic rings, where the radical or point of attachment is on the aliphatic ring.

The term “aryl” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refers to phenyl , 1 -naphthyl, 2-naphthyl, 1-anthracyl And an aromatic ring group having 6 to 14 members such as 2-anthracyl. The term “aryl” also refers to rings that are optionally substituted. The term “aryl” can be used interchangeably with the term “aryl ring”. “Aryl” also includes fused polycyclic aromatic ring systems in which an aromatic ring is fused to one or more rings. Examples include 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scope of the term “aryl” as used herein are those where one aromatic ring is one or more non-aromatic, as in indanyl, phenanthridinyl, or tetrahydronaphthyl. A group that is fused to a ring, where the radical or point of attachment is on the aromatic ring.

  As used herein, the term “heterocycle”, “heterocyclyl”, or “heterocyclic” includes one or more ring carbons, preferably 1 to 4 ring carbons, each by a heteroatom. Included are substituted non-aromatic ring systems having 4 to 14 members, preferably 5 to 10 members. Examples of heterocycles include 3-1H-benzimidazol-2-one, (1-substituted) -2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl , 3-tetrahydropyranyl, 4-tetrahydropyranyl, [1,3] -dioxalanyl, [1,3] -dithiolanyl, [1,3] -dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2 -Morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl , 3-piperidinyl, 4-piperidinyl, 4 Thiazolidinyl, Jiazoroniru, N- substituted Jiazoroniru, 1 Futarimijiniru, Benzokisaniru, benzo pyrrolidinylmethyl, benzo piperidinylmethyl, Benzokisoraniru include Benzochioraniru, and Benzochianiru. Also included within the scope of the terms “heterocyclyl” or “heterocyclic”, as used herein, are non-aromatic hetero, as in indolinyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A group in which an atom-containing ring is fused to one or more aromatic or non-aromatic rings, wherein the radical or point of attachment is on a non-aromatic heteroatom-containing ring. The term “heterocycle”, “heterocyclyl”, or “heterocyclic” also refers to an optionally substituted ring, whether saturated or partially unsaturated.

  The term “heteroaryl” used alone or as part of a larger moiety such as in “heteroaralkyl” or “heteroarylalkoxy” means an aromatic heterocyclic group having 5 to 14 members. Examples of heteroaryl rings include 2-furanyl, 3-furanyl, 3-furazanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- Oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 2-pyrazolyl, 3-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl, 3- Thienyl, carbazolyl, benzimidazolyl Benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indazolyl, isoindolyl, acridinyl, and benzisoxazolyl included. Also included within the scope of the term “heteroaryl”, as used herein, is a group in which an aromatic heterocycle is fused to one or more aromatic or non-aromatic rings, wherein And the radical or point of attachment is on the aromatic heterocycle. Examples include tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido [3,4-d] pyrimidinyl. The term “heteroaryl” also refers to rings that are optionally substituted. The term “heteroaryl” can be used interchangeably with the term “heteroaryl ring” or the term “aromatic heterocycle”.

Aryl group or heteroarylene Le group may include one or more substituents. Examples of suitable substituents on any unsaturated carbon atom of the aryl, heteroaryl, aralkyl, or heteroaralkyl group include halogen, —R ⁰ , —OR ⁰ , —SR ⁰ , 1,2-methylenedioxy , 1,2-ethylenedioxy, protected OH (such as acyloxy), phenyl (Ph), substituted Ph, -O (Ph), substituted _{-O (Ph), - CH 2} (Ph), substituted _-CH 2 (Ph ), —CH ₂ CH ₂ (Ph), substituted —CH ₂ CH ₂ (Ph), NO ₂ , —CN, —N (R ⁰ ) ₂ , —NR ⁰ C (O) R ⁰ , —NR ⁰ C ( O) N (R ⁰ ) ₂ , —NR ⁰ CO ₂ R ⁰ , —NR ⁰ NR ⁰ C (O) R ⁰ , —NR ⁰ NR ⁰ C (O) N (R ⁰ ) ₂ , —NR ⁰ NR ^{0 _{C 2 R 0, -C (O}} ) C (O) R 0, -C (O) CH 2 C (O) _{^{0, -CO 2 R 0, -C}} (O) R 0, -C (O) N (R 0) 2, -OC (O) N (R 0) 2, -S (O) 2 R 0, - _{^{SO 2 N (R 0) 2}} , -S (O) R 0, -NR 0 SO 2 N (R 0) 2, -NR 0 SO 2 R 0, -C (= S) N (R 0) 2, —C (═NH) —N (R ⁰ ) ₂ , — (CH ₂ ) _y NHC (O) R ₀ , and — (CH ₂ ) _y NHC (O) CH (V—R ⁰ ) (R ⁰ ) Each R ⁰ is hydrogen, substituted or unsubstituted aliphatic group, unsubstituted heteroaryl or heterocycle, phenyl (Ph), substituted Ph, —O (Ph), substituted _{-O (Ph), - CH 2} (Ph), or are independently selected from substituted _-CH 2 (Ph); y is an Less than six; V is a linker group A. Examples of the aliphatic group of R ⁰ or a substituent on the phenyl ring include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy , Alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, and haloalkyl.

An aliphatic group or a non-aromatic heterocycle or fused aryl or heteroaryl ring can contain one or more substituents. Examples of suitable substituents on any saturated carbon of an aliphatic group or non-aromatic heterocycle or fused aryl or heteroaryl ring include those listed above for the unsaturated carbon of an aryl or heteroaryl group, and The following: ═O, ═S, ═NNHR ^* , ═NN (R ^* ) ₂ , ═N—, ═NNHC (O) R ^* , ═NNHCO ₂ (alkyl), ═NNHSO ₂ (alkyl), Or = NR ^* , wherein each R ^* is independently selected from hydrogen, an unsubstituted aliphatic group, or a substituted aliphatic group. Examples of substituents on aliphatic groups include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano , Carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, and haloalkyl.

Suitable substituents on the nitrogen of a non-aromatic heterocyclic _{^{ring, -R +, -N (R +}} ) 2, -C (O) R +, -CO 2 R +, -C (O) C (O _{^{) R +, -C (O)}} CH 2 C (O) R +, -SO 2 R +, -SO 2 N (R +) 2, -C (= S) -N (R +) 2, -C (= NH) —N (R ⁺ ) ₂ and —NR ⁺ SO ₂ R ⁺ , where each R ⁺ is hydrogen, aliphatic group, substituted aliphatic group, phenyl (Ph), substituted Ph, -O (Ph), substituted _{-O (Ph), - CH 2} (Ph), are selected from substituted _-CH 2 (Ph), or heteroaryl or heterocyclic ring is unsubstituted independently. Examples of substituents on aliphatic groups or phenyl rings include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, Nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, and haloalkyl are included.

The term “linker group” or “linker” means an organic moiety that connects two parts of a compound. The linker generally consists of an atom such as oxygen or sulfur, a unit such as —NH—, —CH ₂ —, —C (O) —, —C (O) NH—, or a chain of atoms such as an alkylidene chain. The molecular weight of the linker is generally in the range of about 14 to 200, preferably in the range of 14 to 96, and the length is up to about 6 atoms. Examples of linkers include optionally substituted saturated or unsaturated C _1-6 alkylidene chains, wherein one or two saturated carbons of the chain are —C (O) —, —C ( _{O) C (O) -,} - CONH -, - CONHNH -, - CO 2 -, - OC (O) -, - NHCO 2 -, - O -, - NHCONH -, - OC (O) NH -, - NHNH -, - NHCO -, - S -, - SO -, - SO 2 -, - NH -, - SO 2 NH-, or -NHSO ₂ - which is optionally substituted by.

The term "alkylidene chain" completely is saturated, it means a straight or branched carbon chain substituted with arbitrary. Optional substituents are as described above for aliphatic groups.

  Combinations of substituents or variables are permissible only if such combinations result in stable or chemically possible compounds. A stable or chemically feasible compound has a chemical structure when stored in the dark at temperatures below 40 ° C. in the absence of moisture or other chemically reactive conditions for at least a week. It does not change substantially.

  For all substituents defined herein, a polymer that is reached by defining the substituent with a further substituent relative to itself (eg, having a substituted phenyl as a substituent, itself substituted with a substituted phenyl) It is understood that substituted phenyl and the like) are not intended for inclusion herein. In such cases, the maximum number of such substituents is three. For example, phenyl substituted with substituted phenyl is limited to the range -substituted phenyl- (substituted phenyl)-(substituted phenyl).

Unless otherwise indicated, the structures described herein are also intended to include all stereochemical forms of the structures, ie, the R and S configurations for each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless otherwise indicated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically labeled atoms. For example, compounds having this structure are within the scope of this invention except for the replacement of hydrogen with deuterium or tritium, or the replacement of carbon with ¹³ C- or ¹⁴ C-labeled carbon.

  The compound of formula I, or a salt thereof, can be formulated into a composition. In a preferred embodiment, the composition is a pharmaceutical composition. In one embodiment, the composition comprises an amount of a protein kinase inhibitor effective to inhibit protein kinase in a biological sample or patient. Compounds of the invention and pharmaceutical compositions thereof comprising an amount of a protein kinase inhibitor and a pharmaceutically acceptable carrier, adjuvant, or vehicle in an amount effective to treat or prevent a kinase-mediated condition are provided to a patient. It can be formulated for administration.

  Another aspect of the present invention relates to a method for treating or preventing a disease mediated by a kinase. In one embodiment, the disease is a disease mediated by Aurora A and the method administers a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof to a patient in need of such treatment. Including that.

  As used herein, the term “aurora A-mediated disease” or “aurora A-mediated condition” means any disease or other deleterious condition in which aurora is considered to play a role. . The terms “aurora A-mediated disease” or “aurora A-mediated condition” also mean those diseases or conditions that are alleviated by treatment with an Aurora A inhibitor. Such pathologies include cancer.

  The term “cancer” includes, but is not limited to, solid tumors and hematogenous tumors, including but not limited to the following cancers: breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular tumor Urogenital tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratophyte cell carcinoma, lung cancer, squamous cell carcinoma, large cell carcinoma, small cell carcinoma, lung gland Cancer, bone tumor, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular adenocarcinoma, undifferentiated cancer, papillary tumor, seminoma, melanoma, sarcoma, bladder cancer, liver Cancer and bile duct cancer, kidney cancer, bone marrow disorder, lymphatic disorder, Hodgkin's disease, hairy cell leukemia, oral cancer (buccal cavity) and pharyngeal cancer (oral cancer), lip cancer, tongue cancer, oral cancer (mouth) Pharyngeal cancer, small intestine cancer, colorectal cancer, colorectal cancer, rectal cancer, brain and central nervous system cancer, and leukemia It is included. The term “cancer” includes primary cancers, cancers secondary to treatment, and metastatic cancers.

  One aspect of the present invention relates to compounds and compositions useful for treating cancer.

  Another aspect of the present invention is the following cancer: breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular tumor, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, Gastric cancer, skin cancer, keratinous squamous cell carcinoma, lung cancer, squamous cell carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone tumor, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular adenocarcinoma, Undifferentiated cancer, papillary tumor, seminoma, melanoma, sarcoma, bladder cancer, liver and cholangiocarcinoma, kidney cancer, bone marrow disorder, lymphatic disorder, Hodgkin's disease, hairy cell leukemia, oral and pharyngeal cancer, lip It relates to the treatment of cancer, tongue cancer, oral cancer, pharyngeal cancer, small intestine cancer, colorectal cancer, colorectal cancer, rectal cancer, brain tumors and central nervous system cancer, and leukemia.

  Another aspect of the invention is a method of treating cancer comprising administering to a patient with cancer one or more compounds described herein.

  Angiogenesis is characterized by the proliferation of endothelial cells that form new blood vessels (often called angiogenesis). Inhibition of endothelial cell mitosis results in inhibition of angiogenesis. Another aspect of the invention thus relates to the inhibition of unwanted mitosis including unwanted angiogenesis. As defined herein, mammalian diseases characterized by undesirable cellular mitosis include, but are not limited to, excessive or abnormal stimulation of endothelial cells (eg, atherosclerosis), solid tumors and Tumor metastasis, benign tumors such as hemangiomas, acoustic neuromas, neurofibromas, trachoma, and purulent granulomas, vascular dysfunction, abnormal wound healing, inflammatory and immune disorders, Bechet's disease, gout And gouty arthritis, abnormal angiogenesis with rheumatoid arthritis, skin diseases such as psoriasis, diabetic retinopathy, and retinopathy of prematurity (post lens fibroproliferation), macular degeneration, corneal graft rejection, neovascular glaucoma and Ocular vascular diseases such as Osler-Weber syndrome (Osler-Weber-Rendu disease) are included.

  Other undesirable angiogenesis includes normal processes including ovulation and blastocyst implantation. The compositions described above can be used as fertility regulators by reducing or preventing uterine vascularization required for embryo implantation. Thus, the compositions described above can be used to prevent ovulation and blastocyst implantation or to prevent menstruation (inducing amenorrhea).

  Diseases associated with undesirable mitosis, including neovascularization, can be treated according to the present invention. Such diseases include, but are not limited to, ocular neovascular disease, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma and post lens fibrosis, epidemic keratoconjunctivitis, vitamins A deficiency, contact lens fatigue, atopic keratitis, upper limbal keratitis, pterygium dry keratitis, Sjogren's syndrome, acne rosacea, friculosis, syphilis, mycobacterial infection, lipid degeneration, chemical burn, Bacterial ulcer, fungal ulcer, simple herpes simplex infection, herpes zoster infection, protozoal infection, Kaposi sarcoma, Mohren ulcer, peripheral corneal degeneration, peripheral keratolysis, trauma, rheumatoid arthritis, systemic lupus, multiple Arteritis, Wegener sarcoidosis, scleritis, Stevens-Johnson disease, pemphigoid, radial keratotomy, corneal graft rejection.

  Other diseases associated with unwanted mitosis, including neovascularization, can be treated according to the present invention. Such diseases include, but are not limited to, sickle cell anemia, sarcoid, elastic fiber pseudoxanthoma, Paget's disease, venous occlusion, arterial occlusion, carotid obstructive disease, chronic uveitis / Vitreitis, Lyme disease, systemic lupus erythematosus, Eales disease, Behcet's disease, infection causing retinitis or choroiditis, putative ocular histoplasmosis, best disease, myopia, orbital, Stargardt disease, flatitis, chronic retina Includes exfoliation, hyperviscosity syndrome, toxoplasmosis, and post-laser complications. Other diseases are related to lebeosis (iris and corner neovascularization), including but not limited to all forms of proliferative vitreoretinopathy, whether or not related to diabetes Included are diseases and diseases caused by abnormal growth of vascular bundles or fibrous tissue.

  Another aspect of the invention includes, but is not limited to, excessive or abnormal stimulation of endothelial cells (eg, atherosclerosis), solid tumors and tumor metastases, benign tumors such as hemangiomas, acoustic neuromas, nerve fibers , Trachoma, and purulent granulomas, vascular dysfunction, abnormal wound healing, inflammatory and immune disorders, Behcet's disease, gout and gouty arthritis, abnormal angiogenesis with rheumatoid arthritis, skin diseases such as psoriasis, diabetes Retinopathy of the eye and vascular diseases of the eye such as retinopathy of prematurity (post-lens fibroproliferation), macular degeneration, corneal graft rejection, neovascular glaucoma and Osler-Weber syndrome (Osler-Weber-Rendu disease) It relates to the treatment of inflammatory diseases including. Other undesirable angiogenesis includes normal processes including ovulation and blastocyst implantation. Thus, the compositions described above can be used to prevent ovulation and blastocyst implantation or to prevent menstruation (inducing amenorrhea).

  Another aspect of the invention relates to the inhibition of Aurora A activity in a biological sample, the method comprising contacting the biological sample with an Aurora A inhibitor of formula I or a composition thereof.

  Another aspect of the invention relates to a method for inhibiting Aurora A activity in a patient, comprising administering to the patient a compound of formula I or a composition comprising said compound.

  In another aspect of the invention, the compound of formula I is a more potent inhibitor of Aurora A compared to Aurora B.

  Another aspect of the present invention relates to a method of treating or preventing GSK-3 mediated diseases using a GSK-3 inhibitor, which comprises a therapeutically effective amount for a patient in need of such treatment. Administering a compound of formula I or a pharmaceutical composition thereof.

  As used herein, the term “disease mediated by GSK-3” or “disease mediated by GSK-3” refers to any disease or condition in which GSK-3 is known to play a role. Means other harmful conditions or situations. Such diseases or conditions include, but are not limited to, diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS related dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis (MS). ), Schizophrenia, cardiomyocyte hypertrophy, reperfusion / ischemia, and baldness.

  One aspect of the present invention relates to a method for enhancing glycogen synthesis and / or a method for reducing blood glucose levels in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof. Administration of the product. This method is particularly useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated tau protein, which is useful for stopping or delaying the progression of Alzheimer's disease. Another method relates to the inhibition of β-catenin phosphorylation, which is useful in the treatment of schizophrenia.

  Another aspect of the invention relates to the inhibition of GSK-3 activity in a biological sample, the method comprising contacting the biological sample with a GSK-3 inhibitor of formula I.

  Another aspect of the invention relates to a method of inhibiting GSK-3 activity in a patient, comprising administering to the patient a compound of formula I or a composition comprising said compound.

  Another aspect of the invention relates to a method of treating or preventing a CDK-2 mediated disease using a CDK-2 inhibitor, which comprises a therapeutically effective amount for a patient in need of such treatment. Administering a compound of formula I or a pharmaceutical composition thereof.

  As used herein, the terms “disease mediated by CDK-2” or “disease state mediated by CDK-2” refer to any disease or other in which CDK-2 is known to play a role. It means the harmful state of. The terms “CDK-2 mediated disease” or “CDK-2 mediated condition” also mean those diseases or conditions that are alleviated by treatment with a CDK-2 inhibitor. Such conditions include, but are not limited to, cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and rheumatoid arthritis Autoimmune diseases such as Fischer, P. et al. M.M. And Lane, D .; P. , Current Medicinal Chemistry, 7, 1213-1245 (2000); Wang, C .; Wu, K .; Francis, R .; And Pestell, R.A. , Exp. Opin. Invest. Drugs, 9, 1849 (2000); Fry, D .; W. And Garrett, M .; D. , Current Opinion in Oncology, Endocrine & Metabolic Investigative Drugs, 2, 40-59 (2000).

  Another aspect of the present invention relates to the inhibition of CDK-2 activity in a biological sample or patient, the method comprising administering to the patient a compound of formula I or a composition comprising said compound.

  Another aspect of the invention relates to the treatment or prevention of ERK-2 mediated diseases with an ERK-2 inhibitor, which method comprises treating a patient in need of such treatment with a therapeutically effective amount of Formula I. Or a pharmaceutical composition thereof.

  As used herein, the term “ERK-mediated disease” or “ERK-mediated condition” means any disease or other adverse condition in which ERK may play a role. The terms “ERK-2 mediated disease” or “ERK-2 mediated condition” also mean those diseases or conditions that are alleviated by treatment with an ERK-2 inhibitor. Such conditions include, but are not limited to, cancer, stroke, diabetes, liver swelling, cardiovascular disease including cardiac hypertrophy, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune disease, atherosclerosis , Restenosis, psoriasis, allergic disorders including asthma, inflammation, neuropathy, and hormone related diseases. ERK-2 protein kinase and its relationship to various diseases are described in, for example, Bokemeyer et al., 1996, Kidney Int. 49, 1187; Anderson et al., 1990, Nature 343, 651; Crews et al., 1992, Science 258, 478; Bjorbaek et al., 1995, J. Am. Biol. Chem. 270, 18848; Rose et al., 1994, Cell 78, 1027; Raingaud et al., 1996, Mol. Cell Biol. 16, 1247; Raingeauud et al., 1996; Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, 10952; Oliver et al., 1995, Proc. Soc. Exp. Biol. Med. 210, 162; Moodie et al., 1993, Science 260, 1658; Frey and Mulder, 1997, Cancer Res. 57, 628; Sivaraman et al., 1997, J Clin. Invest. 99, 1478; Whelchel et al., 1997, Am. J. et al. Respir. Cell Mol. Biol. 16, 589.

  Another aspect of the present invention relates to the inhibition of ERK-2 activity in a biological sample or patient, the method comprising administering to the patient a compound of formula I or a composition comprising said compound.

  Another aspect of the present invention relates to a method of treatment or prevention using an AKT inhibitor of a disease mediated by AKT, wherein the method comprises a therapeutically effective amount of a compound of formula I in a patient in need of such treatment. Or administering a pharmaceutical composition thereof.

  As used herein, the term “AKT-mediated disease” or “AKT-mediated condition” means any disease or other adverse condition in which AKT is known to play a role. . The terms “AKT-mediated disease” or “AKT-mediated condition” also mean those diseases or conditions that are alleviated by treatment with an AKT inhibitor. Diseases or conditions mediated by AKT include, but are not limited to, proliferative disorders, cancer, and neurodegenerative disorders. The relationship of AKT, also known as protein kinase B, with various diseases is described, for example, in Khwaja, A. et al. , Nature, pp. 33-34, 1990; Zang, Q .; Y. Et al., Oncogene, 19 2000; Kazuhiko, N .; Et al., The Journal of Neuroscience, 20 2000.

  Another aspect of the present invention relates to the inhibition of AKT activity in a biological sample or patient, the method comprising administering to the patient a compound of formula I or a composition comprising said compound.

  Another aspect of the invention relates to a method of treating or preventing a Src-mediated disease using a Src inhibitor, which comprises a therapeutically effective amount of a compound of formula I in a patient in need of such treatment. Or administering a pharmaceutical composition thereof.

  As used herein, the term “Src-mediated disease” or “Src-mediated condition” means any disease or other adverse condition in which Src is known to play a role. . The terms “Src-mediated disease” or “Src-mediated condition” also mean those diseases or conditions that are alleviated by treatment with an Src inhibitor. Such conditions include, but are not limited to, hypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatic treatment of metastasis to bone, and Paget's disease. Src protein kinases and their relationship to various diseases are described, for example, in Soriano, Cell, 69, 551 (1992); Soriano et al., Cell, 64, 693 (1991); Takayanagi, J. et al. Clin. Invest. , 104, 137 (1999); Boschelli, Drugs of the Future 2000, 25 (7), 717, (2000); Talamonti, J. et al. Clin. Invest. 91, 53 (1993); Lutz, Biochem. Biophys. Res. 243, 503 (1998); Rosen, J. et al. Biol. Chem. 261, 13754 (1986); Bolen, Proc. Natl. Acad. Sci. USA, 84, 2251 (1987); Masaki, Hepatology, 27, 1257 (1998); Biscardi, Adv. Cancer Res. 76, 61 (1999); Lynch, Leukemia, 7, 1416 (1993); Wiener, Clin. Cancer Res. 5, 2164 (1999); Staley, Cell Growth Diff. 8, 269 (1997).

  Another aspect of the invention relates to inhibiting Src activity in a biological sample or patient, the method comprising administering to the patient a compound of formula I or a composition comprising said compound.

  Another aspect of the invention relates to a method of treating or preventing a disease mediated by Lck using an Lck inhibitor, wherein the method comprises a therapeutically effective amount of a compound of formula I in a patient in need of such treatment. Or administering a pharmaceutical composition thereof.

  As used herein, the term “Lck-mediated disease” or “Lck-mediated condition” means any disease situation or other adverse condition in which Lck is known to play a role. To do. The terms “Lck-mediated disease” or “Lck-mediated condition” also mean those diseases or conditions that are alleviated by treatment with an Lck inhibitor. Diseases or conditions mediated by Lck include, but are not limited to, autoimmune diseases such as graft rejection, allergies, rheumatoid arthritis, and leukemia. The relationship of Lck with various diseases is described, for example, in Molina et al., Nature, 357, 161 (1992).

  Another aspect of the invention relates to inhibiting Lck activity in a biological sample or patient, the method comprising administering to the patient a compound of formula I or a composition comprising said compound.

  Another aspect of the present invention relates to a method of treatment or prevention using an Ab1 inhibitor of a disease mediated by Ab1, which comprises a therapeutically effective amount of a compound of formula I in a patient in need of such treatment. Or administering a pharmaceutical composition thereof.

  As used herein, the term “Ab1-mediated disease” or “Ab1-mediated condition” means any disease state or other adverse condition in which Ab1 is known to play a role. To do. The terms “Ab1-mediated disease” or “Ab1-mediated condition” also mean those diseases or conditions that are alleviated by treatment with an Ab1 inhibitor. Diseases or conditions mediated by Ab1 include, but are not limited to, leukemia, particularly chronic myeloid leukemia. The relationship between Ab1 and various diseases is described, for example, by Druker et al. Engl. J. et al. Med. 2001, 344, 1038-1042.

  Another aspect of the invention relates to the inhibition of Ab1 activity in a biological sample or patient, the method comprising administering to the patient a compound of formula I, or a composition comprising said compound.

  Another aspect of the invention relates to a method of treating or preventing a cKit-mediated disease using a cKit inhibitor, which comprises a therapeutically effective amount of a compound of formula I in a patient in need of such treatment. Or administering a pharmaceutical composition thereof.

  As used herein, the term “cKit-mediated disease” or “cKit-mediated condition” means any disease state or other adverse condition in which cKit is known to play a role. To do. The terms “cKit-mediated disease” or “cKit-mediated condition” also mean those diseases or conditions that are alleviated by treatment with a cKit inhibitor. Diseases or conditions mediated by cKit include, but are not limited to, mastocytosis / mastocellular leukemia, gastrointestinal stromal tumor, sinus natural killer / T cell lymphoma, seminoma / anaplastic germ cell tumor , Thyroid cancer, small cell lung cancer, malignant melanoma, adenoid cystic cancer, ovarian cancer, acute myeloid leukemia, anaplastic large cell lymphoma, hemangiosarcoma, endometrial cancer, childhood T-cell ALL / lymphoma, breast cancer, and prostate Cancer is included. The relationship between cKit and various diseases is described, for example, in Heinrich et al. Clinical Oncology 2002, 20, 1692-1703.

  Another aspect of the invention relates to the inhibition of cKit activity in a biological sample or patient, the method comprising administering to the patient a compound of formula I, or a composition comprising said compound.

  Another aspect of the present invention relates to a method of treating or preventing Flt3 mediated diseases using a Flt3 inhibitor, which comprises a therapeutically effective amount of a compound of formula I in a patient in need of such treatment. Or administering a pharmaceutical composition thereof.

  As used herein, the term “Flt3-mediated disease” or “Flt3-mediated condition” means any disease state or other adverse condition in which Flt3 is known to play a role. To do. The term “Flt3-mediated disease” or “Flt3-mediated condition” also means those diseases or conditions that are alleviated by treatment with an Flt3 inhibitor. Diseases or conditions mediated by Flt3 include, but are not limited to, acute myeloid leukemia, mixed lineage leukemia, and acute lymphocytic leukemia. The relationship between Flt3 and various diseases is described, for example, by Sternberg and Licht, Curr. Opin Hematol. 2004, 12, 7-13.

  Another aspect of the invention relates to the inhibition of Flt3 activity in a biological sample or patient, the method comprising administering to the patient a compound of formula I, or a composition comprising said compound.

  Another aspect of the present invention relates to a method of treating or preventing a KDR mediated disease using a KDR inhibitor, which comprises a therapeutically effective amount of a compound of formula I in a patient in need of such treatment. Or administering a pharmaceutical composition thereof.

  As used herein, the term “KDR-mediated disease” or “KDR-mediated condition” means any disease state or other adverse condition in which KDR is known to play a role. To do. The terms “KDR-mediated disease” or “KDR-mediated condition” also mean those diseases or conditions that are alleviated by treatment with a KDR inhibitor. Diseases or conditions mediated by KDR include but are not limited to lung cancer, breast cancer, gastrointestinal cancer, kidney cancer, bladder cancer, ovarian cancer and endometrial cancer, intracranial tumors including glioblastoma multiforme , Sporadic capillary hemangioblastoma, T-cell lymphoma, acute lymphocytic leukemia, hematological malignancies including Burkitt lymphoma and promyelocytic leukemia, age-related macular degeneration, herpes eye disease, rheumatoid arthritis, cerebral imagination Blood as well as endometriosis are included. The relationship between KDR and various diseases is described in, for example, Ferrara, Endocrine Reviews 2004, 25, 581-611.

  Another aspect of the invention relates to the inhibition of KDR activity in a biological sample or patient, the method comprising administering to the patient a compound of formula I, or a composition comprising said compound.

  The term “patient” includes human and veterinary subjects.

  The term “biological sample” as used herein includes, but is not limited to, cell cultures or extracts thereof; enzyme preparations suitable for in vitro assays; biopsy materials obtained from mammals or the like Extracts; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

An amount effective to inhibit a protein kinase, such as Aurora A, is an amount that causes measurable inhibition of kinase activity when compared to the activity of the enzyme in the absence of the inhibitor. Any method can be used to determine the inhibitory effect, such as, for example, the biological experimental examples described below.

  The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that can be administered to a patient with a compound of the present invention and does not impair its pharmacological activity. Means.

  Pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions are generally known in the art. These include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum albumin), buffer substances (eg, phosphate), glycine, sorbic acid, potassium sorbate , Partial saturated glyceride mixtures of vegetable saturated fatty acids, water, solvents, salts or electrolytes (eg protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silicates, colloidal silica, three Magnesium silicate, polyvinyl pyrrolidone, cellulosic materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, oil, polyethylene-polyoxypropylene-block polymer, polyethylene glycol, and wool fat. A pharmaceutically acceptable vehicle can comprise a mixture of excipients, where the ingredients and proportions are not limited to, shelf life, stability, drug loading, delivery site, dissolution Selection can be made to optimize the desired properties of the formulation, including rate, self-emulsification, release rate and site control, and metabolism.

  The compositions of the invention are administered orally, parenterally, by inhalation, topically, rectally, nasally, buccally, vaginally, transdermally or via an implanted reservoir. be able to. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, intracranial injection or infusion techniques. included. Preferably, the composition is administered orally, subcutaneously, intraperitoneally, or intravenously.

  The formulation can be prepared by various techniques known in the art. Examples of formulation techniques can be found in literature publications and texts such as “Water-insoluble drug formulation”, Long Liu ed., 2000, Interpharm Press.

  Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and physiological saline. In addition, sterile, fixed oils are commonly used as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid and glyceride derivatives thereof are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated forms. These oils or suspensions are long-chain alcohol diluents or dispersions such as carboxymethylcellulose or similar dispersants commonly used for formulation into pharmaceutically acceptable dosage forms including emulsions and suspensions. Agents can also be included. Other commonly used surfactants such as Tween, Span, and other surfactant emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be formulated It can be used for the purpose of conversion.

  The pharmaceutical compositions of the present invention can be prepared by techniques known in the art and include any orally acceptable including, but not limited to, capsules, tablets, aqueous suspensions or aqueous solutions. It can be administered orally in dosage form. In the case of tablets for oral use, carriers commonly used include, but are not limited to, cellulose, lactose, or corn starch. Lubricants such as magnesium stearate are also commonly added. Diluents or carriers useful for oral administration in a capsule form include lactose and dried corn starch. When aqueous suspensions or solutions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents can also be added.

  Alternatively, the pharmaceutical composition of the invention can be administered in the form of suppositories for rectal administration. These include, for example, mixing the drug with a suitable nonirritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Can be prepared using techniques known in the art. Such materials include cocoa butter, beeswax, and polyethylene glycol.

  The pharmaceutical composition of the present invention may also be administered topically when the subject to be treated contains a region or organ that can be easily reached by topical application, including diseases of the eye, skin, respiratory tract, or lower gastrointestinal tract, among others. it can. Appropriate topical formulations are readily prepared for each of these areas or organs using techniques known in the art. For example, topical application for the lower gastrointestinal tract can be achieved with a rectal suppository formulation (see above) or a suitable enema formulation. Topical transdermal patches can also be used.

  For topical or transdermal application, the pharmaceutical compositions are suitable ointments or bases containing the active ingredients suspended or dissolved in one or more carriers by techniques known in the art. It can be formulated into a base. Carriers for topical administration of the compounds of this invention are well known in the art and include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes. And water. Alternatively, the pharmaceutical composition can be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

  For ophthalmic use, the pharmaceutical composition is as a fine powder or nanometer-size suspension in isotonic pH-adjusted sterile saline, with or without preservatives such as benzylalkonium chloride. Alternatively, it can preferably be formulated as a solution in isotonic pH-adjusted sterile saline by techniques known in the art. Alternatively, for ophthalmology, the pharmaceutical composition can be formulated in an ointment such as petrolatum.

  The pharmaceutical compositions of the invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical arts and include benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or Alternatively, it can be prepared as a suspension or solution in physiological saline, optionally using other conventional solubilizers or dispersants.

  The present invention can be used for the treatment of inflammatory diseases or immune mediated diseases in humans or animals, where the inflammatory diseases or immune mediated diseases include but are not limited to rheumatoid arthritis, osteoarthritis. Ulcerative colitis, Crohn's disease, Mohren ulcer, arthritis, sarcoidosis, inflammatory or immune-mediated bowel disease, systemic lupus, Wegener's syndrome, Stevens-Johnson syndrome, Behcet's disease, pemphigoid, Lyme disease, asthma, Or acquired immune deficiency syndrome.

  The present invention can be used for the treatment of infectious diseases in humans or animals, where the infectious diseases include, but are not limited to, syphilis, bacterial infection, mycobacterial infection, bacterial ulcer, fungal Includes ulcers, herpes simplex infections, herpes zoster infections, protozoal infections, Bartonella infections, or toxoplasmosis.

  The present invention can be used for the treatment of blood or vascular disease in humans or animals, where the blood or vascular disease includes but is not limited to venous occlusion, arterial occlusion, carotid occlusive disease , Polyarteritis, atherosclerosis, Osler-Weber-Rendu disease, sickle cell anemia, leukemia, acute or chronic bone marrow neoplastic disease, hemangioma, hereditary hemorrhagic telangiectasia, bone marrow disease, anemia Reduced blood clotting ability, or swelling of the lymph nodes, liver, or spleen. The present invention can also be used for the treatment of chronic neoplastic diseases of the bone marrow, where these diseases include, but are not limited to, multiple myeloma and myelodysplastic syndrome.

  The present invention can also be used to treat skin conditions in humans or animals, where skin conditions include but are not limited to abnormal wound healing, acne rosacea, chemical burns of the skin, Includes dermatitis or psoriasis.

  Furthermore, the present invention provides various postmenopausal symptoms, osteoporosis, cardiovascular disease, myocardial neovascularization, plaque neovascularization, hemophilia arthropathy, angiofibroma, wound granulation, intestinal adhesion, scleroderma It can be used to treat hypertrophic scars, ie keloids. They are also useful for the treatment of diseases with angiogenesis as a pathological consequence such as cat scratch disease and Helicobacter pylori ulcers. The present invention can also be used as an alternative to treating Alzheimer's disease, reducing the incidence of stroke, and prior estrogen replacement therapy. The compounds of the invention can act by estrogenic and non-estrogenic biochemical pathways.

  In addition, the compounds of the invention can be used to treat endometriosis. Endometriosis is an abnormal proliferation of endometrial cells that line the uterus and are excreted monthly during the menstrual process. Undesirable endometrial cells can be located in areas such as the cecum, rectal vaginal septum, stomach, fallopian tubes, ovaries, and bladder in the lower abdomen. During menstruation, the normal uterine lining is peeled off and expelled through the vagina, but the migrated endometrial tissue has no means of exiting the body, instead the endometrial tissue and cells are located Adheres and proliferates at the place where The result is internal bleeding, inflammation, and scarring. A serious consequence of endometrial scarring is infertility. Endometrial proliferation is generally not malignant or cancerous. Among other complications, the proliferated tissue can rupture and can spread endometriosis to new areas of the lower abdomen. Endometriosis is a progressive disease. Proliferating tissue or lesions initially appear as clear blisters, then turn red and eventually progress to black lesions over a period of 7 to 10 years.

  Furthermore, the compounds of the present invention can be formulated to increase the bioavailability of the compounds by methods well known to those skilled in the art. Formulation methods and examples of formulations of the compounds of the present invention are described in “Water-Instable Drug Formulation” edited by Long Liu, CRC Press LLC, 2000, which is incorporated herein by reference in its entirety.

  Formulations contemplated as part of the present invention include manufactured by controlled precipitation methods and methods disclosed in US Patent Application 10 / 392,403 (Publication 2004/0033267), which is hereby incorporated by reference in its entirety. Nanoparticle formulations to be included. Common excipients for nanoparticles known in the art include surfactants such as water, sugar polymers (modified cellulose) and detergents, as well as optionally benzalkonium salts, benzoes Acids or salts thereof, or preservatives such as parabens are included. By forming nanoparticles, the compositions disclosed herein increased bioavailability. Preferably, the particles of the compound of the invention have a particle size of less than about 2 microns, less than about 1900 nm, less than about 1800 nm as measured by light scattering, microscopy, or other suitable methods well known to those skilled in the art. Less than 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm Less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, or less than about 50 nm. Nanoparticle preparations are for example suspensions or creams or ointments for topical or transdermal administration, suspensions or powders for suppositories or oral administration or tablets or capsules or pellets, suspensions for sterile injectable preparations. It can be incorporated into many of the formulation techniques described herein, including liquids and polymer formulations.

  The compounds making up the present invention can be mixed with biodegradable or non-biodegradable polymers to allow sustained release of the compounds. The polymer can be implanted such that the drug is delivered parenterally into the body, or a polymer comprising a compound that constitutes the invention can be implanted around the tumor. For an overview of polymers in controlled drug delivery, see, for example, “Biodegradable Polymers as Drug Delivery Systems”, Chasin M and Langer R (eds), New York, Marcel Dekker, 1990, which is incorporated herein by reference in its entirety. Can be found in Another review can be found in “Handbook of Biodegradable Polymers”, D.C. Weseman, J .; Kost and A.K. Domb, Taylor & Francis, 1998 (incorporated herein by reference in its entirety).

  A “pharmaceutically acceptable derivative or prodrug” is a compound of the invention that can provide a compound of the invention or an inhibitory active metabolite or residue thereof, either directly or indirectly, when administered to a recipient. Means any pharmaceutically acceptable salt, ester, amide, ester or amide salt, or other derivative of the compound. Particularly preferred derivatives or prodrugs increase the bioavailability of the compounds of the present invention when such compounds are administered to a patient compared to the parent species (eg, orally administered compounds are easier in the blood). Or the delivery of the parent compound to the biological compartment (eg, brain or lymphatic system).

  Pharmaceutically acceptable prodrugs of the compounds of this invention include, but are not limited to, the following derivatives of this compound: esters, amino acid esters, amino acid amides, phosphate esters, metal salts, sulfonate esters, Carbamates and amides are included.

  Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, Ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfo Narate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3- E nil propionate, phosphate, picrate, pivalate, propionate, include salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate. Although not pharmaceutically acceptable per se, other acids such as oxalic acid should be used in the preparation of salts useful as intermediates to obtain the compounds of the invention and their pharmaceutically acceptable acid addition salts. Can do.

Salts derived from appropriate bases include alkali metal (eg, sodium and potassium), alkaline earth metal (eg, magnesium), ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Products that are soluble or dispersible in water or oil can be obtained by such quaternization.

  The amount of protein kinase inhibitor that can be combined with the carrier material to produce a single dosage form will vary depending upon the patient being treated and the particular mode of administration. Preferably, the composition should be formulated so that a dose of 0.01-100 mg / kg body weight / day of inhibitor can be administered to patients receiving these compositions.

  The specific dose and treatment regimen for any particular patient is the activity, age, weight, general health, sex, dietary habits, time of administration, rate of elimination, drug combination, It is also to be understood that this will depend on various factors including the judgment of the treating physician and the severity of the particular disease being treated. The amount of inhibitor also depends on the particular compound in the composition.

  Depending on the condition mediated by the particular protein kinase to be treated or prevented, additional therapeutic agents normally administered to treat or prevent the condition can be administered with the inhibitors of the present invention. For example, in the treatment of cancer, other kinase inhibitors, chemotherapeutic agents, anti-angiogenic agents, antiemetics, colony stimulating factors, or other anti-proliferative agents treat the cancer as is known in the art. Therefore, it can be combined with the present compound. These agents include, but are not limited to, bevacizumab, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxane, interferon, and platinum derivatives.

  Other examples of agents that may be combined with the inhibitors of the present invention include, but are not limited to, insulin or insulin analogs in injection or inhalation forms, glitazones, alpha glucosidase inhibitors, biguanides, insulin resistance ameliorating agents, And therapeutic agents for diabetes such as sulfonylureas; anti-inflammatory drugs such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon , Immunomodulators and immunosuppressants such as corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ioncha Neurotrophic factors such as tunnel blockers, riluzole, and anti-parkinsonian drugs; β-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and treatments for cardiovascular diseases such as statins; corticosteroids; Treatment for liver diseases such as cholestyramine, interferon, and antiviral drugs; Treatment for blood disorders such as corticosteroids, anti-leukemia drugs, and growth factors; therapeutic antibodies such as bevacizumab; and immunodeficiency disorders such as gamma globulin Therapeutic drugs are included.

  These additional agents can be administered separately from the composition comprising the protein kinase inhibitor or as part of a multiple dose schedule. Alternatively, the agents may be part of a single dosage form mixed with the protein kinase inhibitor of the present invention in a single composition.

The compounds of the present invention can exist in alternative tautomeric forms, for example the tautomers shown below. Unless otherwise indicated, the representation of any tautomer is intended to include any other tautomer.

In one embodiment, the present invention provides a compound of formula I, or a pharmaceutically acceptable derivative or prodrug thereof.

[Where:
R ^x and R ^y are independently selected from the group consisting of —T—R ³ and —L—Z—R ³ ;
Q ′ is −CR ⁶ ″ = CR ⁶ ″ − and

Is selected from the group consisting of, wherein said -CR 6 ^"= CR 6" ^- may be a cis or trans double bonds or mixtures thereof;
R ¹ is -T- (Ring D);
Ring D is a 5-7 membered monocyclic or 8-10 membered bicyclic ring selected from the group consisting of aryl, heteroaryl, heterocyclyl, and carbocyclyl, wherein the heteroaryl or heterocyclyl ring is nitrogen, oxygen, and It has 1-4 ring heteroatoms selected from the group consisting of sulfur, wherein each substitutable ring carbon of ring D is oxo, -T-R 5 or ^{-V-Z-R, 5} is substituted independently by each substitutable ring nitrogen of ring D is independently substituted by R ^4;
T is a valence bond or — (C (R ^{6 ′} ) ₂ ) —A—;
A is a valence bond or _C 1 -C ₃ alkylidene chain, wherein said _C 1 -C ₃ methylene units of the alkylidene chain, -O -, - S -, - N (R 4) -, - _{CO -, - CONH -, -} NHCO -, - SO 2 -, - SO 2 NH -, - NHSO 2 -, - CO 2 -, - OC (O) -, - OC (O) NH-, or -NHCO ₂ - which is optionally substituted by;
Z is a C _1-4 alkylidene chain;
L _{is, -O -, - S -,} - SO -, - SO 2 -, - N (R 6) SO 2 -, - SO 2 N (R 6) -, - N (R 6) -, - CO _{^{-, - CO 2 -, -}} N (R 6) CO -, - N (R 6) C (O) O -, - N (R 6) CON (R 6) -, - N (R 6) SO 2 N (R ⁶ ) —, —N (R ⁶ ) N (R ⁶ ) —, —C (O) N (R ⁶ ) —, —OC (O) N (R ⁶ ) —, —C (R ⁶ ) _{^{2 O -, - C (R}} 6) 2 -, - C (R 6) 2 SO -, - C (R 6) 2 SO 2 -, - C (R 6) 2 SO 2 N (R 6) -, _{^{-C (R 6) 2 N (}} R 6) -, - C (R 6) 2 N (R 6) C (O) -, - C (R 6) 2 N (R 6) C (O) O- ^{, -C (R 6) = NN} (R 6) -, - C (R 6) = N-O -, - C (R 6) 2 N (R 6 ) N (R ⁶ ) —, —C (R ⁶ ) ₂ N (R ⁶ ) SO ₂ N (R ⁶ ) —, and —C (R ⁶ ) ₂ N (R ⁶ ) CON (R ⁶ ) —. Selected from the group;
R ² and R ^{2 ′} are independently selected from the group consisting of —R and —T—W—R ⁶ , or R ² and R ^{2 ′} together with the atoms between them, nitrogen, oxygen And forms a fused, 5- to 8-membered, unsaturated or partially unsaturated ring having 0 to 3 ring heteroatoms selected from the group consisting of sulfur and R ² and R ^{2 ′} Each substitutable ring carbon of the fused ring formed by is independently substituted by halo, oxo, —CN, —NO ₂ , R ⁷ , or —V—R ⁶ , and R ² and R ² Each substitutable ring nitrogen of said ring formed by ^' is independently substituted by -R ⁴ ;
R ³ is —R, —halo, —OR, —C (═O) R, —CO ₂ R, —COCOR, —COCH ₂ COR, —NO ₂ , —CN, —S (O) R, —S. (O) ₂ R, —SR, —N (R ⁴ ) ₂ , —CON (R ⁷ ) ₂ , —SO ₂ N (R ⁷ ) ₂ , —OC (═O) R, —N (R ⁷ ) COR _{^{, -N (R 7) CO 2}} (C 1~6 _{^{aliphatic), - N (R 4)}} N (R 4) 2, -C = NN (R 4) 2, -C = N-OR, -N ^{(R 7)} consisting of _{^{CON (R 7) 2, -N}} (R 7) SO 2 N (R 7) 2, -N (R 4) SO 2 R, and -OC (= O) N (R ) 2 Selected from the group;
Each R consists heterocyclyl ring having independently hydrogen or _{C 1 to 6 aliphatic,, C 6 to 10} aryl, heteroaryl ring having 5 to 10 ring atoms, and 5 to 10 ring atoms An optionally substituted group selected from the group;
Each R ⁴ is independent of the group consisting of —R ⁷ , —COR ⁷ , —CO ₂ (optionally substituted C _1-6 aliphatic), —CON (R ⁷ ) ₂ , and —SO ₂ R ^7. Is selected;
Each R ⁵ is —R, halo, —OR, —C (═O) R, —CO ₂ R, —COCOR, —NO ₂ , —CN, —S (O) R, —SO ₂ R, — SR, —N (R ⁴ ) ₂ , —CON (R ⁴ ) ₂ , —SO ₂ N (R ⁴ ) ₂ , —OC (═O) R, —N (R ⁴ ) COR, —N (R ⁴ ) CO _{2 (C 1 to 6} aliphatic optionally _{^{substituted), - N (R 4)}} N (R 4) 2, -C = NN (R 4) 2, -C = N-OR, -N (R ⁴ ) CON (R ⁴ ) ₂ , —N (R ⁴ ) SO ₂ N (R ⁴ ) ₂ , —N (R ⁴ ) SO ₂ R, and —OC (═O) N (R ⁴ ) ₂ Independently selected from;
V _{is, -O -, - S -,} - SO -, - SO 2 -, - N (R 6) SO 2 -, - SO 2 N (R 6) -, - N (R 6) -, - CO _{^{-, - CO 2 -, -}} N (R 6) CO -, - N (R 6) C (O) O -, - N (R 6) CON (R 6) -, - N (R 6) SO 2 N (R ⁶ ) —, —N (R ⁶ ) N (R ⁶ ) —, —C (O) N (R ⁶ ) —, —OC (O) N (R ⁶ ) —, —C (R ⁶ ) ₂ O—, —C (R ⁶ ) ₂ S—, —C (R ⁶ ) ₂ SO—, —C (R ⁶ ) ₂ SO ₂ —, —C (R ⁶ ) ₂ SO ₂ N (R ⁶ ) — _{^{, -C (R 6) 2 N}} (R 6) -, - C (R 6) 2 N (R 6) C (O) -, - C (R 6) 2 N (R 6) C (O) O ^{-, - C (R 6)} = NN (R 6) -, - C (R 6) = N-O -, - C (R 6) 2 N (R _{^{6) N (R 6) -}} , - C (R 6) 2 N (R 6) SO 2 N (R 6) -, and _{^{-C (R 6) 2 N (}} R 6) CON (R 6) - from Selected from the group consisting of:
W represents —C (R ⁶ ) ₂ O—, —C (R ⁶ ) ₂ S—, —C (R ⁶ ) ₂ SO—, —C (R ⁶ ) ₂ SO ₂ —, —C (R ⁶ ). _{^{2 SO 2 N (R 6)}} -, - C (R 6) 2 N (R 6) -, - CO -, - CO 2 -, - C (R 6) OC (O) -, - C (R 6 _{^{) OC (O) N (R}} 6) -, - C (R 6) 2 N (R 6) CO -, - C (R 6) 2 N (R 6) C (O) O -, - C (R ⁶ ) = NN (R ⁶ )-, -C (R ⁶ ) = N-O-, -C (R ⁶ ) ₂ N (R ⁶ ) N (R ⁶ )-, -C (R ⁶ ) ₂ N ( Selected from the group consisting of R ⁶ ) SO ₂ N (R ⁶ ) —, —C (R ⁶ ) ₂ N (R ⁶ ) CON (R ⁶ ) —, and —CON (R ⁶ ) —;
Each R ⁶ is independently selected from the group consisting of hydrogen and optionally substituted C _1-4 aliphatic groups, or two R ⁶ groups on the same nitrogen atom together with the nitrogen atom Can form a 5-6 membered heterocyclyl or heteroaryl ring;
Each R ^{6 ′} is independently selected from the group consisting of hydrogen and C _1-4 aliphatic groups, or two R ^{6 ′} on the same carbon atom are taken together to form a 3-6 membered carbocycle Forming;
Each R ^{6 ″} is independently selected from the group consisting of hydrogen, C _1-4 aliphatic groups, halogen, optionally substituted aryl, and optionally substituted heteroaryl, or on adjacent carbon atoms Two R ^{6 ″} together form a 5-7 membered carbocyclic or heterocyclic ring, or one of R ^{6 ″} together with a substituent on ring D is a fused bicyclic Forming a carbocyclic or heterocyclic ring;
Each R ⁷ is independently selected from the group consisting of hydrogen and optionally substituted C _1-6 aliphatic groups, or two R ⁷ on the same nitrogen together with the nitrogen 5 Forms an 8-membered heterocyclyl or heteroaryl ring].

In one embodiment, the present invention provides a compound of formula Ia, or a pharmaceutically acceptable derivative or prodrug thereof.

^{Wherein, R 2, R 2 ',} R x, R y, and ^{R 1} are similarly defined as in Formula I; ^{Q a} is cis or trans ^{-CR 6 "= CR} 6" - or mixtures thereof Each R ^{6 ″} is independently selected from hydrogen, methyl, halogen, optionally substituted aryl, and optionally substituted heteroaryl.

In certain embodiments, the present invention is, ^{Q a} trans ^{-CR 6 "= CR} 6" - provides compounds of formula Ia.

In another embodiment, this invention provides a compound of formula Ib, or a pharmaceutically acceptable derivative or prodrug thereof.

[Wherein R ² , R ^{2 ′} , R ^x , R ^y , and R ¹ are defined as in Formula I, and Q ^b is

Is].

Preferred R ^x groups in compounds of formula I, Ia, Ib, II, IIa, and IIb include hydrogen, alkyl, amino, nitro, alkyl or dialkylamino, acetamide, or methyl, ethyl, cyclopropyl, or isopropyl Contains C _1-4 aliphatic groups, most preferably hydrogen and amino.

Preferred R ^y groups in compounds of formula I, Ia, Ib, II, IIa, and IIb include —T—R ³ or —L—Z—R ³ , where T is a valence bond or alkyl (1 to 6 carbon chains in length, branched or unbranched) or alkene (1 to 6 carbon chains in length, branched or unbranched), L is —O—, —S— , —C (R) ₂ O—, —CO—, —C (O) N (R ⁶ ) —, or —N (R ⁴ ) —, and R ³ is —R, —N (R ⁴ ) _2. Or OR. Preferred R ^y groups include 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, hydroxypiperidinyl, N- (4-hydroxypiperidin) -yl, O- (4-piperidinyl), piperazinyl , Alkylpiperazinyl, or 4-methylpiperazinyl, N-acetylpiperidinyl, N-alkylcarboxamidopiperidinyl, N- (methylsulfone) piperidinyl, thiophene, furan, tetrahydrofuran, cyclo [2.2.1 A 5-6 membered heteroaryl or non-aromatic heterocycle such as heptenyl; a C _1-6 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl; an alkoxyalkylamino such as methoxyethylamino; Or an alcohol such as methoxyethyl Amino, alkyl- or dialkylamino such as ethylamino or dimethylamino; alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy; acetamide; alkoxycarbonyl; alkyl- and dialkylamidocarbonyl; and phenyl or halo-substituted phenyl, etc. Optionally substituted phenyl is included. For amine nitrogen, N may be in the free base form, pharmaceutically acceptable salt, or quaternary salt. The present invention contemplates that R ³ can be bonded to L or T through either a heteroatom or any ring atom, if there is a hydrogen available for ring bonding.

R ² and R ^{2 ′} together can form a fused ring to provide a bicyclic system including a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, partially unsaturated 6-membered carbocycle, wherein the fused ring is optionally substituted. Fused 5-membered rings are also envisioned and include, but are not limited to, pyrrolo, tetrahydrofuran, tetrahydrothiofuran, imidazolidine, and pyrazolidine. These are exemplified in the compounds of formula I below having a pyrazole-containing bicyclic system, but also apply to compounds of formulas Ia and Ib.

Preferred substituents on R ² / R ^{2 'fused} ring include those of one or more of the following, namely, - _{^{halo, -N (R 4) 2,}} -C 1~3 _{alkyl, -C 1 to 3} Haloalkyl, —NO ₂ , —O (C _1-3 alkyl), —CO ₂ (C _1-3 alkyl), —CN, —SO ₂ (C _1-3 alkyl), —SO ₂ NH ₂ , —OC ( O) NH ₂ , —NH ₂ SO ₂ (C _1-3 alkyl), —NHC (O) (C _1-3 alkyl), —C (O) NH ₂ , and —CO (C _1-3 alkyl) Included, where (C _1-3 alkyl) is most preferably methyl.

When the pyrazole ring system is monocyclic, preferred R ² groups include hydrogen, C _1-4 aliphatic, alkoxycarbonyl, (un) substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl , Aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (N-heterocyclyl) carbonyl. Examples of such preferred R ² substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO ₂ H, CO ₂ CH ₃ , CH ₂ OH, CH ₂ OCH ₃ , CH ₂ CH ₂ CH ₂ OH, CH ₂ CH ₂ CH ₂ OCH ₃ , CH ₂ CH ₂ CH ₂ OCH ₂ Ph, CH ₂ CH ₂ CH ₂ NH ₂ , CH ₂ CH ₂ CH ₂ NHCOOC (CH ₃ ) ₃ , CONHCH _{(CH 3) 2, CONHCH 2} CH = CH 2, CONHCH 2 CH 2 OCH 3, CONHCH 2 Ph, CONH ( _{cyclohexyl), CON (Et) 2,} CON (CH 3) CH 2 Ph, CONH (n-C 3 _{H 7), CON (Et)} CH 2 CH 2 CH 3, CONHCH 2 CH (CH 3) 2 _{, CON (n-C 3 H} 7) 2, CO (3- methoxymethyl-1-yl), CONH (3- tolyl), CONH (4-tolyl), CONHCH _3, CO (morpholin-1-yl) , CO _{(4-methylpiperazin-1-yl),} CONHCH ₂ CH _{2 OH,} include CONH _2, and CO (piperidin-1-yl) it is. A preferred R ^{2 ′} group is hydrogen.

  When ring D of formula I, Ia, or Ib is monocyclic, preferred ring D groups include optionally substituted phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

  When ring D of formula I, Ia, or Ib is bicyclic, preferred optionally substituted bicyclic D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzoyl [B] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl, and isoquinolinyl.

On ring D of formula I, Ia, or Ib, preferred T—R ⁵ or V—Z—R ⁵ substituents include —halo, —CN, —NO ₂ , —N (R ⁴ ) ₂ , optionally substituted _{C 1 to 6} aliphatic ^{_{group, -OR, -C (O) R}} , -CO 2 R, -CONH (R 4), - N (R 4) COR, -N (R 4) CO 2 R _{^{, -SO 2 N (R 4)}} 2, -N (R 4) SO 2 R, -N (R 6) COCH 2 N (R 4) 2, -N (R 6) COCH 2 CH 2 N (R 4 ) ₂ , and —N (R ⁶ ) COCH ₂ CH ₂ CH ₂ N (R ⁴ ) ₂ , where R is hydrogen, C _1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring Or a 5-6 membered heterocycle. _More preferred ^{R 5} substituents, -Cl, -Br, -F, -CN , -CF 3, -COOH, -CONHMe, -CONHEt, -NH 2, -NHAc, -NHSO 2 Me, -NHSO 2 Et , -NHSO ₂ (n-propyl), - NHSO _{2 (isopropyl), - NHCOEt, -NHCOCH 2 NHCH} 3, -NHCOCH 2 N (CO 2 t-Bu) CH 3, -NHCOCH 2 N (CH 3) 2, _{-NHCOCH 2 CH 2 N (CH 3} ) 2, -NHCOCH 2 CH 2 CH 2 N (CH 3) 2, -NHCO ( cyclopropyl), - NHCO (isobutyl), - NHCOCH ₂ (morpholin-4-yl), -NHCOCH ₂ CH _{2 (morpholin-4-yl), - NHCOCH 2 CH 2 CH} 2 ( morpholin-4-y ), - NHCO ₂ (t- _butyl), -NH _{(C 1~4} aliphatic such as NHMe), - -N such NMe _{2 (C 1 to 4 aliphatic)} 2, OH, -O, such as -OMe _{(C 1 to 4} aliphatic), methyl, ethyl, _{C 1 to 4} aliphatic, such as cyclopropyl, isopropyl or t- butyl, and _-CO 2 _{(C 1 to 4} aliphatic) include.

Preferred compounds of formula I are
(A) R ^x is hydrogen, nitro, amino, alkyl- or dialkylamino, acetamide, or a C _1-4 aliphatic group;
(B) R ^y is —T—R ³ or —L—Z—R ³ , where T is a valence bond or — (C (R ^{6 ′} ) ₂ ) —, and R ³ is —R, _{^{-N (R 4) 2, -OR}} , or is -CO ₂ R;
(C) R ¹ is —T— (Ring D), where T is a valence bond or — (C (R ^{6 ′} ) ₂ ) —;
(D) Ring D is an optionally substituted 5-7 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
(E) R ² is —R or —T—W—R ⁶ , R ^{2 ′} is hydrogen, or R ² and R ^{2 ′} together form an optionally substituted benzene ring;
(F) each R ^{6 ″} is independently hydrogen, a C _1-4 aliphatic group, a halogen, an optionally substituted aryl, or an optionally substituted heteroaryl; Have two, three, four, five, or all.

More preferred compounds of formula I are
(A) R ^y is —T—R ³ or —L—Z—R ³ , where T is a valence bond or — (C (R ^{6 ′} ) ₂ ) —, and R ³ is —R, —OR, —N (R ⁴ ) ₂ , or —CO ₂ R, where R is hydrogen, C _1-6 aliphatic, 5-6 membered heterocyclyl, 6 membered aryl, or 5-6 membered heteroaryl. is there;
(B) R ¹ is —T— (Ring D), where T is a valence bond or — (C (R ^{6 ′} ) ₂ ) —;
(C) Ring D is an optionally substituted 5-6 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
(D) R ² is —R and R ^{2 ′} is hydrogen, where —R is independently hydrogen, or C _1-6 aliphatic, C _6-10 aryl, 5-10 ring atoms. An optionally substituted group selected from the group consisting of a heteroaryl ring having a heterocyclyl ring having 5 to 10 ring atoms;
(E) L is —O—, —S—, —N (R ⁴ ) —, or —C (O) N (R ⁶ ) —;
(F) Q 'transformer ^{-CR 6 "= CR} 6" is - or

Is
(G) each R ^{6 ″} is independently hydrogen, methyl, halogen, optionally substituted aryl, or optionally substituted heteroaryl; one, two, three, or any of the features selected from the group consisting of Have four, five, six or all.

Even more preferred compounds of formula I are:
(A) R ^x is hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, amino, dimethylamino, methylamino, nitro, or acetamide;
(B) R ^y is 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, hydroxypiperidinyl, N- (4-hydroxypiperidinyl) -yl, O- (4-piperidinyl), piperazinyl, alkylpiperazinyl 4-alkylpiperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamide, optionally substituted phenyl, methoxy Selected from methyl, —CO ₂ R, and —C (O) N (R ⁶ ) ZR;
(C) R ¹ is —T— (Ring D), wherein T is a valence bond, Ring D is a 5-6 membered aryl or heteroaryl ring, wherein Ring D is —halo, CF ₃ , ^{_{-CN, -NO 2, -N (R}} 4) 2, optionally substituted _{C 1 to 6} aliphatic ^{_{group, -OR, -CO 2 R, -CONH}} (R 4), - N (R 4) COR _{^{, -N (R 4) SO 2}} R, -N (R 4) COCH 2 N (R 6) 2, -N (R 4) COCH 2 CH 2 N (R 6) 2, and -N ^(R 4) Optionally substituted with one or two groups selected from COCH ₂ CH ₂ CH ₂ N (R ⁶ ) ₂ ;
(D) R ² is hydrogen or substituted or unsubstituted C _1-6 aliphatic;
(E) Q 'transformer ^{-CR 6 "= CR} 6" is - or

Is
(F) Each R 6 ″ is independently hydrogen, methyl, chloro, or fluoro, having one, two, three, four, five, or all of the characteristics selected from the group consisting of:

Particularly more preferred compounds of formula I are
(A) R ^x is hydrogen or amino;
(B) R ^y is 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, hydroxypiperidinyl, N- (4-hydroxypiperidinyl) -yl, O- (4-piperidinyl), piperazinyl, alkylpiperazinyl , 4-alkylpiperazinyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, optionally substituted phenyl, —CO ₂ R, and —C (O) NHZR ;
(C) R ¹ is T- (Ring D), where T is a valence bond, Ring D is a 5-6 membered aryl or heteroaryl ring, wherein Ring D is -halogen, -CN , —CF ₃ , —NO ₂ , —N (R ⁴ ) ₂ , optionally substituted C _1-6 aliphatic groups, —OR, —CO ₂ R, —CONH (R ⁴ ), —N (R ^{4 _{) COR -, - N (R}} 4) SO 2 R, -N (R 4) COCH 2 N (R 6) 2, -N (R 4) COCH 2 CH 2 N (R 6) 2, and -N ( Optionally substituted by one or two groups selected from R ⁴ ) COCH ₂ CH ₂ CH ₂ N (R ⁶ ) ₂ ;
(D) R ² is hydrogen or substituted or unsubstituted C _1-6 aliphatic and L is —O—, —S—, —NH—, or —C (O) NH—. ;
(E) Q 'is trans ^{-CR 6 "= CR} 6" - is;
(F) Each R ^{6 ″} is independently hydrogen or fluoro having one, two, three, four, five or all of the features selected from the group consisting of

Preferred compounds of formula Ia or Ib are
(A) R ^x is hydrogen, nitro, amino, alkyl- or dialkylamino, acetamide, or a C _1-4 aliphatic group;
(B) R ^y is —T—R ³ or —L—Z—R ³ , where T is a valence bond or — (C (R ^{6 ′} ) ₂ ) —, and R ³ is —R, _{^{-N (R 4) 2, -OR}} , or is -CO ₂ R;
(C) R ¹ is —T— (Ring D), where T is a valence bond or — (C (R ^{6 ′} ) ₂ ) —;
(D) Ring D is a 5-7 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
(E) R ² is —R or —T—W—R ⁶ , R ^{2 ′} is hydrogen, or R ² and R ^{2 ′} together form an optionally substituted benzene ring;
(F) each R ^{6 ″} is independently hydrogen, a C _1-4 aliphatic group, a halogen, an optionally substituted aryl, or an optionally substituted heteroaryl; Have two, three, four, five or all.

More preferred compounds of formula Ia or Ib are
(A) R ^y is —T—R ³ or —L—Z—R ³ , where T is a valence bond or — (C (R ^{6 ′} ) ₂ ) —, and R ³ is —R, —OR, —N (R ⁴ ) ₂ , or —CO ₂ R, where R is hydrogen, C _1-6 aliphatic, 5-6 membered heterocyclyl, 6 membered aryl, or 5-6 membered heteroaryl. is there;
(B) R ¹ is —T— (Ring D), where T is a valence bond or — (C (R ^{6 ′} ) ₂ ) —;
(C) Ring D is a 5-6 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
(D) R ² is —R and R ^{2 ′} is hydrogen, where —R is independently hydrogen, or C _1-6 aliphatic, C _6-10 aryl, 5-10 ring atoms. An optionally substituted group selected from the group consisting of a heteroaryl ring having a heterocyclyl ring having 5 to 10 ring atoms;
(E) L is —O—, —S—, —N (R ⁴ ) —, or —C (O) N (R ⁶ ) —;
(F) each R ^{6 ″} is independently hydrogen, methyl, halogen, optionally substituted aryl, or optionally substituted heteroaryl. Have one, four, five or all.

Even more preferred compounds of formula Ia or Ib are
(A) R ^x is hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, amino, dimethylamino, methylamino, nitro, or acetamide;
(B) Ry is 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, hydroxypiperidinyl, N- (4-hydroxypiperidinyl) -yl, O- (4-piperidinyl), piperazinyl, alkylpiperazinyl, 4-alkylpiperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamide, optionally substituted phenyl, methoxy Selected from methyl, —CO ₂ R, and —C (O) N (R ⁶ ) ZR;
(C) R ¹ is -T- (Ring D), where T is a valence bond, Ring D is a 5-6 membered aryl or heteroaryl ring, where Ring D is -halo, CF ₃ , —CN, —NO ₂ , —N (R ⁴ ) ₂ , optionally substituted C _1-6 aliphatic groups, —OR, —CO ₂ R, —CONH (R ⁴ ), —N (R ⁴ ) COR, —N (R ⁴ ) SO ₂ R, —N (R ⁴ ) COCH ₂ N (R ⁶ ) ₂ , —N (R ⁴ ) COCH ₂ CH ₂ N (R ⁶ ) ₂ , and —N (R) ⁴⁾ it is optionally substituted by one or two groups selected from ^{_{COCH 2 CH 2 CH 2 N (}} R 6) 2;
(D) R ² is hydrogen or substituted or unsubstituted C _1-6 aliphatic;
(E) Each R ^{6 ″} is independently hydrogen, methyl, chloro, or fluoro, having one, two, three, four, or all of the characteristics selected from the group consisting of

Particularly preferred compounds of formula Ia or Ib are
(A) R ^x is hydrogen or amino;
(B) R ^y is 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, hydroxypiperidinyl, N- (4-hydroxypiperidinyl) -yl, O- (4-piperidinyl), piperazinyl, alkylpiperazinyl , 4-alkylpiperazinyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, optionally substituted phenyl, —CO ₂ R, and —C (O) NHZR ;
(C) R ¹ is -T- (Ring D), where T is a valence bond, Ring D is a 5-6 membered aryl or heteroaryl ring, wherein Ring D is -halogen,- CN, —CF ₃ , —NO ₂ , —N (R ⁴ ) ₂ , optionally substituted C _1-6 aliphatic group, —OR, —CO ₂ R, —CONH (R ⁴ ), —N (R _{^{4) COR, -N (R 4}} ) SO 2 R, -N (R 4) COCH 2 N (R 6) 2, -N (R 4) COCH 2 CH 2 N (R 6) 2, and -N ( Optionally substituted by one or two groups selected from R ⁴ ) COCH ₂ CH ₂ CH ₂ N (R ⁶ ) ₂ ;
(D) R ² is hydrogen or substituted or unsubstituted C _1-6 aliphatic and L is —O—, —S—, —NH—, or —C (O) NH—. ;
(E) Each R ^{6 ″} is independently hydrogen or fluoro having one, two, three, four or all of the characteristics selected from the group consisting of

In another embodiment, this invention provides a compound of formula II, or a pharmaceutically acceptable derivative or prodrug thereof.

[Where:
R ^x is hydrogen, nitro, amino, alkyl- or dialkylamino, acetamide, or a C _1-4 aliphatic group;
R ^y is 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-alkylpiperazinyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, optionally substituted Phenyl, —CO ₂ R, or —C (O) NHZR, wherein R is hydrogen, C _1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; is an _C 1 -C ₄ alkylidene chain;
Q ′ is −CR ^{6 ″} = CR ^{6 ″} − or

, And the ^{where, -CR 6 "= CR 6"} - may be a cis or trans double bond; each R ^{6 "is} independently hydrogen, aryl substituted methyl, halogen, optionally or optionally, A heteroaryl substituted with
R ¹ is —halogen, —CN, —CF ₃ , —NO ₂ , —N (R ⁴ ) ₂ , optionally substituted C _1-6 aliphatic group, —OR, —CO ₂ R, —CONH (R _{^{4), - N (R 4}} ) COR, -N (R 4) SO 2 R, -N (R 4) COCH 2 N (R 6) 2, -N (R 4) COCH 2 CH 2 N (R 6 ) ₂ , and —N (R ⁴ ) COCH ₂ CH ₂ CH ₂ N (R ⁶ ) ₂ , optionally substituted with one or two groups selected from the group consisting of R, R ⁴ and R ⁶ are defined as in Formula I].

In certain embodiments, the present invention provides a compound of formula I or II wherein Q ′ is trans —CH═CH—. In another embodiment, Q ′ is

It is.

In other embodiments of compounds of Formula I or II, R ^x is hydrogen.

In still other embodiments, R ^y is 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, hydroxypiperidinyl, N- (4-hydroxypiperidin) -yl, O- (4-piperidinyl), piperazinyl, alkyl piperazinyl, 4-alkylpiperazinyl, alkoxyalkylamino, alkoxyalkyl, alkyl - or dialkyl amino, alkyl - or dialkyl aminoalkoxy, optionally substituted phenyl, -CO 2 _R, and -C ( O) Selected from NHZR.

In certain embodiments, R ^y is 4-alkylpiperazinyl. In other embodiments, R ^y is 4-methylpiperazinyl.

In certain embodiments, R ^y is hydroxypiperidinyl. In other embodiments, R ^y is N- (4-hydroxypiperidin) -yl or O- (4-piperidinyl).

In one embodiment, the present invention provides a compound of formula IIa, or a pharmaceutically acceptable derivative or prodrug thereof.

^{Wherein, R x,} R ^y, and ^{R 1} are defined as in the formula II; ^{Q a} is cis or trans ^{-CR 6 "= CR} 6" - or mixtures thereof; each ^{R 6 "} Are independently selected from hydrogen, methyl, halogen, optionally substituted aryl, and optionally substituted heteroaryl.

In certain embodiments of compounds of Formula IIa, Q ^a is cis —CR ^{6 ″} ═CR ^{6 ″} —.

In other embodiments, ^{Q a} is trans ^{-CR 6 "= CR} 6" - a.

In one embodiment, the present invention provides a compound of formula IIa, or a pharmaceutically acceptable derivative or prodrug thereof.

[Wherein R ^x , R ^y , and R ¹ are as defined in Formula II, and Q ^b is

Is].

In certain embodiments, the present invention provides a compound of formula I, Ia, Ib, II, IIa, or IIb, wherein R ¹ is selected from the following groups:

[Here the line drawn through the side of the substituent indicates that the substituent can be attached to the linker at any ring atom if there is hydrogen available for substitution].

In certain embodiments of compounds of Formula I, Ia, Ib, II, IIa, or IIb, R ^x is hydrogen.

In some embodiments of the compound of formula I, Ia, Ib, II, IIa, or IIb, R ^y is 4-methylpiperazinyl.

In certain embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, R ^y is N- (4-hydroxypiperidin) -yl or O- (4-piperidinyl).

In other embodiments of the compounds of formula I, Ia, Ib, II, IIa, or IIb, R ¹ is phenyl.

In yet other embodiments, the invention provides a compound shown in Table 1, or a pharmaceutically acceptable salt, derivative, or prodrug thereof.

  In one embodiment, the present invention provides a composition comprising a compound of formula I and a pharmaceutically acceptable carrier. In certain such embodiments, the composition is for the treatment or prevention of disorders mediated by kinases.

  In another embodiment, the invention relates to a method of treating or preventing a disease mediated by a kinase, said method comprising a therapeutically effective amount of a compound of formula I, or a medicament thereof, in a patient in need of such treatment. Administering a composition.

  In certain embodiments of the above methods and compositions, the disorder is mediated by Aurora A, Aurora B, CDK-2, ERK-2, AKT, Src, Lck, Ab1, cKit, Flt3, or KDR. In other aspects, the disorder is mediated by Aurora A, Src, Lck, Ab1, cKit, Flt3, or KDR.

  Another aspect of the invention relates to a method of inhibiting Aurora A activity in a patient, comprising administering to the patient a compound of formula I or a composition comprising said compound.

  Another aspect of the invention relates to a method of treating or preventing a GSK-3 mediated disease using a GSK-3 inhibitor, which comprises a therapeutically effective amount for a patient in need of such treatment. Administering a compound of formula I or a pharmaceutical composition thereof.

  One aspect of the present invention relates to a method for enhancing glycogen synthesis and / or a method for reducing blood glucose levels in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I, or a pharmaceutical composition thereof. Administration of the product. This method is particularly useful for diabetic patients. Another method relates to the inhibition of the production of hyperphosphorylated tau protein, which is useful for stopping or delaying the progression of Alzheimer's disease. Another method relates to the inhibition of β-catenin phosphorylation useful in the treatment of schizophrenia.

  Another aspect of the invention relates to a method of inhibiting GSK-3 activity in a patient comprising administering to the patient a compound of formula I, or a composition comprising said compound.

  Another aspect of the invention relates to a method of treating or preventing a Src-mediated disease using a Src inhibitor, which comprises a therapeutically effective amount of a compound of formula I in a patient in need of such treatment. Or administering a pharmaceutical composition thereof.

  Another aspect of the invention relates to the inhibition of Src activity in a patient, the method comprising administering to the patient a compound of formula I, or a composition comprising said compound.

  Another method relates to the inhibition of Aurora A, GSK-3, or Src activity in a biological sample, which method comprises in the biological sample an amount of Formula I effective to inhibit Aurora 2, GSK-3, or Src. Contacting aurora A, GSK-3, or Src inhibitor comprising the compound or pharmaceutical composition thereof.

  Each of the above methods directed to the inhibition of Aurora A, GSK-3, or Src, or treatment of a disease thereby reduced, preferably uses a preferred compound of formula I as described above. Implemented.

The invention also relates to methods for preparing the compounds of the invention and synthetic intermediates useful in such methods, as described below and in the examples.

  In another aspect of the invention, preferred embodiments of Formula 1-K can be synthesized as shown in Scheme 1, wherein the variable substituents are as described above, and Examples are illustrated by Table 1, where —Ar is a defined optionally substituted aryl or heteroaryl group, which examples are illustrated by Table 1. Dihydroxypyrimidine 1-A is dissolved in about 1 to 20 volumes of trifluoroacetic acid and treated with about 1 to 5 equivalents of nitric acid at about −20 to 30 ° C. for about 30 minutes to 24 hours. The resulting nitropyrimidine 1-B is about 1 to 20 equivalents of optionally substituted aromatic or heteroaromatic aldehyde 1-C and about 1 to 20 equivalents of organic at about 20 to 120 ° C. for about 30 minutes to 24 hours. Treatment with a base, preferably piperidine, gives vinylpyrimidine 1-D. Treatment of vinylpyrimidine 1-D with about 2 to 20 equivalents of phosphorus oxychloride and about 2 to 5 equivalents of a tertiary organic base, preferably diethylaniline, at about 0 to 200 ° C. for about 30 minutes to 24 hours. To give dichloropyrimidine 1-E. Tertiary dichloropyrimidine 1-E in a suitable solvent such as (but not limited to) tetrahydrofuran, such as (but not limited to) about 1 to 10 equivalents of triethylamine at about 0 to 65 ° C. for about 30 minutes to 24 hours. Treatment with organic base and about 1 equivalent of aminopyrazole 1-F provides aminopyrimidine 1-G. Subsequently, 1-G in a suitable solvent, such as but not limited to tetrahydrofuran, is added at about 0 to 65 ° C. for about 30 minutes to 24 hours, about 1 to 10 equivalents of triethylamine and the like (but not limited to). Treatment with a primary organic base and about 1 to 5 equivalents of primary or secondary amine 1-H provides diaminopyrimidine 1-J. Diaminopyrimidine 1-J is dissolved in a suitable solvent such as but not limited to methanol at about 0 to 65 ° C. for about 30 minutes to 24 hours, and about 2 to 10 equivalents of tin (II) chloride in dilute hydrochloric acid. Or added to a suitable chemical reducing agent such as but not limited to titanium (III) chloride to give triaminopyrimidine 1-K.

In another aspect of the invention, preferred embodiments of Formula 2-F are prepared as shown in Scheme 2, wherein the variable substituents are as described above, and this example is It is indicated by 1. A solution of about 1 to 5 equivalents of aminopyrazole 2-B in a suitable solvent, such as but not limited to dioxane, at about 0 to 60 ° C. for about 15 minutes to 24 hours, such as but not limited to dioxane Is added to a solution of dichloropyrimidine 2-A and about 1 to 10 equivalents of an appropriate organic base, preferably 2,6-lutidine, in a suitable solvent to give chloropyrimidine 2-C. Chloropyrimidine 2-C, about 1 to 5 equivalents of sodium carbonate, potassium carbonate, or cesium carbonate in a suitable solvent such as but not limited to toluene or tetrahydrofuran at about 20 to 150 ° C. for about 30 minutes to 24 hours About 1 to 5 equivalents of optionally substituted cis- or transaryl- or heteroaryl-vinylboronic acid 2-D, about 0.01 to 1 equivalent of tetrakis (triphenylphosphine) palladium, etc. Vinylpyrimidine 2-E is obtained by mixing a palladium catalyst. A solution of vinylpyrimidine 2-E in a suitable solvent such as, but not limited to, dimethyl sulfoxide, acetic acid, or acetonitrile is added to about 2 to 20 equivalents of zinc powder and ammonium formate, tin (II) chloride or titanium chloride ( Treatment with a chemical reducing agent such as (but not limited to) III) provides aminopyrimidine 2-F. Aminopyrimidine 2-F can be either cis or trans depending on whether each of the cis or trans isomers of aryl- or heteroaryl-vinylboronic acid is used in the reaction pathway.

  In another aspect of the invention, preferred embodiment 2-H is prepared as shown in Scheme 2, wherein aminopyrimidine 2-F is prepared at about 0 to 150 ° C. for about 1 to 48 hours. Treat with about 1 to 100 equivalents of alcohol 2-G and about 0.1 to 5 equivalents of titanium (IV) isopropoxide or potassium cyanide alone or in a suitable solvent.

In another aspect of the invention, preferred embodiment 2-K is prepared as shown in Scheme 2, wherein aminopyrimidine 2-F is added to dichloromethane at 0-30 ° C. for about 1-48 hours. Treatment with about 1 to 20 equivalents of amine 2-J and about 1 to 20 equivalents of trimethylaluminum in a suitable solvent such as, but not limited to.

In another aspect of the invention, preferred embodiments of Formula 3-E are prepared as shown in Scheme 3, wherein the variable substituents are as described above. A solution of about 1 to 5 equivalents of aminopyrazole 3-B in a suitable solvent, such as but not limited to dioxane, at about 0 to 60 ° C. for about 15 minutes to 24 hours, such as but not limited to dioxane Is added to a solution of dichloropyrimidine 3-A and about 1 to 10 equivalents of an appropriate organic base, preferably 2,6-lutidine, in a suitable solvent to give chloropyrimidine 3-C. Chloropyrimidine 3-C, about 1 to 5 equivalents of sodium carbonate, potassium carbonate, or carbonic acid in a suitable solvent such as but not limited to toluene or tetrahydrofuran at about 20 to 150 ° C. for about 30 minutes to 24 hours Inorganic base such as (but not limited to) cesium, about 1 to 5 equivalents of optionally substituted cis- or trans-aryl- or heteroaryl-vinylboronic acid 3-D, about 0.01 to 1 equivalent of tetrakis- Vinylpyrimidine 3-E is obtained by mixing a palladium catalyst such as (but not limited to) (triphenylphosphine) -palladium. Vinylpyrimidine 3-E is either cis or trans depending on whether the cis or trans isomer of aryl- or heteroaryl-vinylboronic acid is used in the reaction.

  In another aspect of the invention, preferred embodiments 4-H are prepared as shown in Scheme 4, wherein the variable substituents are as described above, and examples are given according to Table 1. It is shown. Thiomethylpyrimidine 4-A in a suitable solvent such as but not limited to dichloromethane is about 2 to 10 equivalents of 3-chlorobenzoyl peroxide (mCPBA) at about 0 to 30 ° C. for about 30 minutes to 24 hours, etc. Treatment with (but not limited to) an oxidizing agent provides sulfonylpyrimidine 4-B. The sulfonylpyrimidine 4-B in a suitable solvent such as but not limited to tetrahydrofuran is replaced with about 1 to 5 equivalents of optionally substituted aryl- or heteroaryl at about −50 to 30 ° C. for about 1 to 24 hours. Treatment with acetylenylmagnesium halide 4-C gives propargyl pyrimidine 4-D. Propargylpyrimidine 4-D in a suitable solvent such as (but not limited to) dimethylacetamide is about 1 to 2 equivalents of aminopyrazole 4-E, 1 to 5 equivalents at about 0 to 140 ° C. for about 1 to 24 hours. Treatment with a tertiary organic base such as but not limited to about 1 to 5 equivalents of diisopropylethylamine to give monochloropyrimidine 4-F. Monochloropyrimidine 4-F in a suitable solvent, such as but not limited to dioxane, is about 1 to 5 equivalents of primary or secondary amine 4-G, about 0. Treatment with a tertiary organic base such as, but not limited to, 01 to 1 equivalent of 4-dimethylaminopyridine and about 1 to 5 equivalents of diisopropylethylamine provides aminopyrimidine 4-H.

  In another aspect of the invention, preferred embodiments 4-J are prepared as shown in Scheme 4, where aminopyrimidine 4-H in a suitable solvent such as but not limited to tetrahydrofuran. Is treated with about 0.8 to 1.1 equivalents of lithium aluminum hydride at about −10 to 30 ° C. for about 1 to 24 hours to give trans-styrylpyrimidine 4-J.

In another aspect of the invention, preferred embodiments 4-K are prepared as shown in Scheme 4, where aminopyrimidines in a suitable solvent such as but not limited to ethyl acetate or methanol 4-H is treated with about 0.1 to 1 equivalent of Lindlar catalyst, about 0.1 to 2 equivalents of quinoline, and about 1 atmosphere of hydrogen gas to give cis-styrylpyrimidine 4-K.

  In another aspect of the invention, preferred embodiments 5-D and 5-E are prepared as shown in Scheme 5, wherein the variable substituents are as described above, and An example is shown by Table 1. The sulfonylpyrimidine 4-B in a suitable solvent such as but not limited to tetrahydrofuran is substituted with about 1 to 2 equivalents of optionally substituted cis- or trans at about −50 to 30 ° C. for about 30 minutes to 24 hours. Treatment with 2-aryl- or heteroaryl-vinylmagnesium halide 5-A provides dichloropyrimidine 5-B. Dichloropyrimidine 5-B in a suitable solvent such as (but not limited to) dimethylacetamide is about 1 to 2 equivalents of aminopyrazole 4-E, about 1 to 5 at about 20 to 140 ° C. for about 1 to 24 hours. Treatment with an equivalent amount of sodium iodide and a tertiary organic base such as but not limited to about 1 to 5 equivalents of diisopropylethylamine provides monochloropyrimidine 5-C. Monochloropyrimidine 5-C in a suitable solvent such as (but not limited to) dioxane is about 1 to 5 equivalents of primary or secondary amine 4-G,. Treatment with a tertiary organic base such as, but not limited to, 05 to 1 equivalent of 4-dimethylaminopyridine, and about 1 to 5 equivalents of diisopropylethylamine 5-vinyl magnesium halide 5- Depending on whether A is either the trans- or cis-isomer, either styrylpyrimidine 5-D or 5-E is obtained.

In another aspect of the invention, preferred embodiment 6-G is prepared as shown in Scheme 6, wherein the variable substituents are as described above, and this example is It is shown in the figure. Selected examples of 6-G are shown by Table 1.

R—X—H in Scheme 6 can be selected from the following structures, for example.

The moiety labeled “Ar” in Scheme 6 can be selected, for example, from the following structure, where the line drawn through the side of the substituent indicates that the “Ar” substituent is substituted Indicates that when there is hydrogen available, it can be attached to the alkene linker or alkyne linker at any ring atom.

The optionally substituted or fused-ring aminopyrazole “Pz—NH 2” in Scheme 6 can be selected, for example, from the following structures:

  Product 6-G from Scheme 6 can be produced by selection of a nitrile having an Ar-substituent selected from the examples described above or shown in the above figure. These nitrites are either commercially available or known to those skilled in the art including, for example, but not limited to the conversion of the appropriate aldehyde to acrylonitrile using related reactions such as, but not limited to, the Wittig reaction or the Peterson olefination reaction. Can be produced by the reaction. In general, the desired product is selected, for example, based on the above description, or selecting an appropriate Pz-NH2 selected from the above figure showing examples of Pz-NH2, and for example, in the above description It is also made by selecting R—X—H selected based on or selected from the above diagram showing examples of R—X—H. Examples of possible products are shown in Table 1. The present invention also includes molecule 6-G, for which the reagents for both coupling reactions shown in Scheme 6 are selected from Pz-NH2.

Nitrile 6-A Ar—CR ^{6 ″} = CR ^{6 ″} —CN or Ar—CC—CN is usually dissolved in 1 to 100 times volume of solvent, for example a mixture of absolute toluene and absolute ethanol. The solution is usually cooled from 0 ° C. to −70 ° C. and dry hydrogen chloride gas is blown in for 1 to 24 hours, after which the reaction is stopped and stirred for 1 to 72 hours, usually from −20 ° C. to room temperature. Workup of this reaction mixture provides O-ethyl imidate 6-B or an alkynyl analog thereof that can be isolated as the HCl salt. The 6-B or alkyl analog is dissolved in a solvent containing, for example, but not limited to ethanol, and cooled usually between room temperature and -20 ° C., and anhydrous ammonia in alcohol (eg, methanol or ethanol or a mixture) Add the solution. Anhydrous ammonia solution can be purchased commercially or freshly prepared by bubbling ammonia gas through a suitable solvent. The mixture is generally stirred at a temperature of 0 ° C. to 50 ° C., generally for 1 to 24 hours. This mixture is worked up to give 6-C or its alkynyl analog.

The 6-C or alkynyl analog is dissolved in a solvent containing (but not limited to) 1 to 10 weight equivalents of methanol. A malonic ester derivative containing dimethyl malonate (generally but not limited to 0.75 to 5 molar equivalents) is added to the solution, usually at a temperature of 0 ° C to 50 ° C. The mixture is generally cooled from −20 ° C. to room temperature and a base, including but not limited to, for example, NaOCH ₃ (usually 2 to 10 equivalents), is generally added slowly for 1 to 120 minutes. The resulting solution is heated to a temperature suitable for the solvent selected and is generally heated or refluxed for 1 to 24 hours. Post-treatment provides 6-D or its alkynyl analog.

The 6-D or alkynyl analog is added slowly in small portions to an excess of chlorinating reagent, including but not limited to POCl ₃ . One skilled in the art can optionally use a chlorinating agent such as POCl ₃ as the solvent and reactant, or a chlorinating agent as the reactant, optionally including, but not limited to, acetonitrile. ) A solvent can be selected. One skilled in the art can use bases, including but not limited to, Hunig base (diisopropylethylamine) or other amine bases to improve the effectiveness of the reaction. The mixture is generally stirred for 1 to 24 hours, usually 75 ° C to 130 ° C. The reaction mixture is worked up and purified to give 6-E or its alkynyl analog.

  The 6-E or alkynyl analog is then coupled to the desired substituent. As shown in the scheme, when the selected substituents are, for example, Pz—NH 2 and R—X—H selected from the attached figures, Pz—NH 2 is first coupled via 6-F. R—X—H can be attached, or R—X—H can be attached first, and Pz—NH 2 can be attached via 6-H. If the desired product has two substituents selected from Pz-NH2, the appropriate reaction conditions described below are used.

  To bind Pz-NH2, for example, a solution of 6-E or 6-H or an alkynyl analog thereof in a solvent containing (but not limited to) anhydrous DMA (usually 1 to 100 equivalents) is used in the present invention. Usually 0.5 to 5 equivalents of aminopyrazole, which can be selected from the description, and optionally a reagent containing, for example, NaI or a catalyst, and optionally a base containing (but not limited to) DIPEA are added. The mixture is generally stirred at a temperature of 50 ° C. to 90 ° C. for usually 2 to 36 hours. Work-up and purification yields 6-F or 6-G, or an alkynyl analog thereof, respectively.

  In order to bind R—X—H, 6-E or 6-F or an alkynyl analog thereof is dissolved in the desired R—X—H and is generally 0.25 to 12 at 50 ° C. to 110 ° Heat for hours. Optionally, a solvent containing (but not limited to) anhydrous DMA can be selected, as well as optionally including a base including (but not limited to) DIPEA or TEA, and optionally including NaI or a catalyst. Reagents (but not limited to) can be used to facilitate the reaction. Workup and purification provide the target compound 6-H or 6-G, or an alkynyl analog thereof, respectively.

  Alternative coupling methods to those shown in Scheme 6, such as the addition of a base including but not limited to TEA or DIPEA, and similarly the replacement of one or both chlorine atoms with, for example, iodine or bromine, and the like In addition, the use of catalysts, including but not limited to heavy metal catalysts such as palladium complexes or Cu (I), can be used to increase the effectiveness or selectivity of the reaction for a particular RXH. These techniques are well known to those skilled in the art and include, for example, Gomtsian et al. (J. Med. Chem. 2002 45, 3639) and publications such as US Pat. No. 5,453,414, which are incorporated herein by reference in their entirety. Has been reported to things. Further variations may be achieved by the use of coupling reactions including, but not limited to, Suzuki, Stille, Grignard, and Buchwald known to those skilled in the art. Optionally, appropriate protecting groups can be added and removed to facilitate the reaction, as is known to those skilled in the art. Examples of other coupling reactions can be found in “Strategic Applications of Named Reactions in Organic Synthesis” (L. Kurti and B. Czako, Elesier Academic Press, New York, NY, 2005). Examples of protecting groups can be found in literature that can include "Protective Groups in Organic Synthesis-Third Edition" (TW Greene, PMGM Wuts, Wiley-Interscience, New York, NY, 1999). .

  The invention will be more readily understood by reference to the following examples, which are provided for purposes of illustration and are not intended to limit the invention.

(Example)
The following abbreviations are used in the examples.

ATP: adenosine triphosphate Brij-35: polyoxyethylene glycol dodecyl ether ° C: Celsius temperature DMEM: Dulbecco's modified eagle medium DMSO: dimethyl sulfoxide DTT: dithiothreitol g: gram HEPES: 4- (2-hydroxyethyl) piperazine- 1-ethanesulfonic acid hplc: high performance liquid chromatography IC ₅₀ value: concentration of inhibitor that causes a 50% reduction in measured activity mg: milligram mL: milliliter mmol: mmol MS: mass spectrum m / z: mass vs. charge Ratio Pz: arbitrarily modified or substituted or fused pyrazole ring system Rf: ratio to tip (ratio of distance traveled by the substance / distance traveled by the solvent)
SRB: Sulforhodamine B
TCA: Trichloroacetic acid THF: Tetrahydrofuran tlc thin layer chromatography br broad s singlet d doublet t triplet q quartet dd double doublet J binding constant (Example 1)

2-Methyl-5-nitropyrimidine-4,6-diol 4,6-dihydroxy-2-methylpyrimidine powder (9 g, 71 mmol) was dissolved in trifluoroacetic acid (54 mL). The reaction mixture was cooled in ice water while nitric acid (4.3 mL) was added dropwise over 30 minutes. During the addition, the internal temperature was kept below 15 ° C. After the addition, cooling was stopped and the reaction was stirred overnight. Water (50 mL) was added to the reaction mixture and the resulting solid was filtered and dried under vacuum to give 2-methyl-5-nitropyrimidine-4,6-diol (5.8 g). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.97 (br, 2H), 2.32 (s, 3H). MS (m / z) 172 (M + l).

(Example 2)

5-nitro-2-[(E) -2-phenylvinyl] pyrimidine-4,6-diol 2-methyl-5-nitropyrimidine-4,6-diol (4.7 g, 27.5 mmol) and benzaldehyde (42 mL) 414 mmol) was treated with piperidine (21.3 mL, 215.3 mmol). The reaction mixture was heated at 90 ° C. for 2 hours. The temperature was then raised to 120 degrees for 30 minutes. After the reaction mixture was cooled to ambient temperature, methanol (10 mL) and diethyl ether (200 mL) were added sequentially. The obtained solid was collected by filtration and washed with 5% aqueous hydrochloric acid to give 5-nitro-2-[(E) -2-phenylvinyl] pyrimidine-4,6-diol (4.5 g). . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.15 (d, 1H, J = 16.4 Hz), 7.15 (m, 2H), 7.54 (m, 3H), 6.81 ( d, 1H, J = 16.4 Hz). MS (m / z) 260 (M + l).

(Example 3)

4,6-dichloro-5-nitro-2-[(E) -2-phenylvinyl] pyrimidine 5-nitro-2-[(E) -2-phenylvinyl] pyrimidine-4,6-diol (2.4 g , 9.63 mmol) was treated with phosphorus oxychloride (10 mL, 106.6 mmol) followed by the dropwise addition of diethylaniline (4 mL, 25.1 mmol; a slight exotherm was observed during the addition). The reaction mixture was slowly heated to 200 ° C. After 1.5 hours, the reaction was cooled and poured into crushed ice with stirring. The resulting solid was collected by filtration and dried to give 4,6-dichloro-5-nitro-2-[(E) -2-phenylvinyl] pyrimidine (1.6 g). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.15 (d, 1H, J = 16.4 Hz), 7.89 (m, 2H), 7.47 (m, 3H), 7.37 ( d, 1H, J = 16.4 Hz). MS (m / z) 296 (M + l).

Example 4

6- (4-Methylpiperazin-1-yl) -N- (3-methyl-1H-pyrazol-5-yl) -5-nitro-2-[(E) -2-phenylvinyl] pyrimidin-4-amine To a solution of 4,6-dichloro-5-nitro-2-[(E) -2-phenylvinyl] pyrimidine (200 mg, 0.676 mmol) in THF (5 mL) was added triethylamine (204 mg, 2.03 mmol). The reaction mixture was stirred for 15 minutes. 3-Amino-5-methyl-pyrazole (66 mg, 0.68 mmol) in THF (3 mL) was added dropwise to the reaction mixture. After 1 hour, N-methylpiperazine (74 mg, 0.74 mmol) in THF (3 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour before water (10 mL) was added. After stirring for 15 minutes, ethyl acetate (50 mL) was added. The organic layer was separated and dried, and the solvent was evaporated under reduced pressure. The residue was triturated in chloroform and hexane to give 6- (4-methylpiperazin-1-yl) -N- (3-methyl-1H-pyrazol-5-yl) -5-nitro-2-[(E)- 2-Phenylvinyl] pyrimidin-4-amine (80 mg) was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.35 (br, 1H), 10.52 (br, 1H), 7.95 (d, 1H, J = 16 Hz), 7.83 (d, 2H, J = 6.8 Hz), 7.5 (m, 3H), 7.11 (d, 1H, J = 16 Hz), 6.8 (s, 1H), 3.65 (br, 4H), 2 .5 (br, 4H), 2.36 (s, 3H), 2.29 (s, 3H). MS (m / z) 421 (M + 1).

  Examples 5-9 were prepared in the same manner as Example 4 by replacing N-methylpiperazine with the appropriate amine.

(Example 5)

N, N′-bis (3-methyl-1H-pyrazol-5-yl) -5-nitro-2-[(E) -2-phenylvinyl] pyrimidine-4,6-diamine N-methylpiperazine was converted to 3- N, N′-bis (3-methyl-1H-pyrazol-5-yl) -5-nitro-2-[(E) -2-phenylvinyl] pyrimidine-4 by replacing with amino-5-methylpyrazole , 6-diamine was obtained in 44% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.41 (br, 2H), 11.35 (br, 2H), 7.92 (d, 1H, J = 16 Hz), 7.79 (d, 1H, J = 6.8 Hz), 7.76 (m, 3H), 7.16 (d, 1H, J = 16 Hz), 6.80 (s, 2H), 2.31 (s, 6H). MS (m / z) 418 (M + l).

(Example 6)

N- (3-methyl-1H-pyrazol-5-yl) -5-nitro-6- (morpholin-4-yl) -2-[(E) -2-phenylvinyl] pyrimidin-4-amine N-methyl By replacing piperazine with morpholine, N- (3-methyl-1H-pyrazol-5-yl) -6- (morpholin-4-yl) -5-nitro-2-[(E) -2-phenylvinyl] Pyrimidin-4-amine was obtained in 15% yield after preparative high performance liquid chromatography. ¹ H NMR (400 MHz, CDCl ₃ ): δ 10.56 (br, 1H), 7.88 (d, 1H, J = 16 Hz), 7.65 (d, 2H, J = 6.8 Hz), 7. 40 (m, 3H), 7.06 (d, 1H, J = 16 Hz), 6.38 (s, 1H), 3.83 (m, 4H), 3.69 (m, 4H), 2.37 (S, 3H). MS (m / z) 408 (M + l).

(Example 7)

N- (3-methyl-1H-pyrazol-5-yl) -5-nitro-6- (piperazin-1-yl) -2-[(E) -2-phenylvinyl] pyrimidin-4-amine N-methyl By replacing piperazine with piperazine, N- (3-methyl-1H-pyrazol-5-yl) -5-nitro-6- (piperazin-1-yl) -2-[(E) -2-phenylvinyl] Pyrimidin-4-amine was obtained in 17% yield after preparative hplc. ¹ H NMR (400 MHz, CDCl ₃ ): δ 10.58 (br, 1H), 7.87 (d, 1H, J = 16 Hz), 7.62 (m, 2H), 7.38 (m, 3H) 6.96 (d, 1H, J = 16 Hz), 6.37 (s, 1H), 3.74 (m, 4H), 3.58 (m, 4H), 2.36 (s, 3H). MS (m / z) 407 (M + l).

(Example 8)

N- (3-methyl-1H-pyrazol-5-yl) -5-nitro-6- (piperidin-1-yl) -2-[(E) -2-phenylvinyl] piperidin-4-amine N-methyl By replacing piperazine with piperidine, N- (3-methyl-1H-pyrazol-5-yl) -5-nitro-6- (piperidin-1-yl) -2-[(E) -2-phenylvinyl] Piperidin-4-amine was obtained in 16% yield after preparative hplc. ¹ H NMR (400 MHz, CDCl ₃ ): δ 10.58 (br, 1H), 7.87 (d, 1H, J = 16 Hz), 7.62 (m, 2H), 7.38 (m, 3H) 6.95 (d, 1H, J = 16 Hz), 6.35 (s, 1H), 3.58 (m, 4H), 2.36 (s, 3H), 1.4 to 1.9 (m , 6H). MS (m / z) 406 (M + 1).

Example 9

N- (3-methyl-1H-pyrazol-5-yl) -5-nitro-6- (pyrrolidin-1-yl) -2-[(E) -2-phenylvinyl] pyrimidin-4-amine N-methyl By replacing piperazine with pyrrolidine, N- (3-methyl-1H-pyrazol-5-yl) -5-nitro-6- (pyrrolidin-1-yl) -2-[(E) -2-phenylvinyl] Pyrimidin-4-amine was obtained in 14% yield after preparative chromatography. ¹ H NMR (400 MHz, CDCl ₃ ): δ 10.5 (br, 1H), 7.9 (d, 1H, J = 16 Hz), 7.65 (m, 2H), 7.39 (m, 3H) 7.13 (d, 1H, J = 16 Hz), 6.29 (s, 1H), 2.5 to 3.5 (m, 4H), 2.37 (s, 3H), 2.02 (m , 4H). MS (m / z) 392 (M + l).

(Example 10)

6- (4-Methylpiperazin-1-yl) -N- (3-methyl-1H-pyrazol-5-yl) -2-[(E) -2-phenylvinyl] pyrimidine-4,5-diamine concentrated hydrochloric acid A solution of tin (II) chloride dihydrate (600 mg, 4.43 mmol) in (1 mL, 9.04 mmol) was cooled to below 10 ° C. 6- (4-Methylpiperazin-1-yl) -N- (3-methyl-1H-pyrazol-5-yl) -5-nitro-2-[(E) -2-phenylvinyl in methanol (20 mL) A solution of pyrimidine-4-amine (Example 4, 400 mg, 0.95 mmol) was added dropwise to the reaction mixture. The reaction was brought to ambient temperature and then heated at 60 ° C. for 3 hours. The progress of the reaction was monitored by TLC. The reaction mixture was reduced to 1/3 of the original volume under vacuum. The residue was diluted with ethyl acetate (40 mL) and 1N NaOH (20 mL) was added to the reaction mixture. The organic layer was separated and dried, and the solvent was evaporated under reduced pressure. The residue was then triturated in ethyl acetate and hexane to give 6- (4-methylpiperazin-1-yl) -N- (3-methyl-1H-pyrazol-5-yl) -2-[(E) -2 -Phenylvinyl] pyrimidine-4,5-diamine (200 mg) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.94 (br, 1H), 7.70 (d, 1H, J = 16 Hz), 7.59 (m, 2H) 7.38 (m, 2H) ), 7.29 (m, 1H), 7.05 (d, 1H, J = 16 Hz), 6.36 (br, 1H), 3.44 (br, 2H), 3.3 (br, 4H) 2.59 (br, 4H), 2.36 (s, 3H), 2.33 (s, 3H). MS (m / z) 391 (M + 1).

  Examples 11 to 15 were prepared from the appropriate starting materials in the same manner as Example 10.

(Example 11)

N, N′-bis (3-methyl-1H-pyrazol-5-yl) -2-[(E) -2-phenylvinyl] pyrimidine-4,5,6-triamine N, N′- of Example 5 Bis (3-methyl-1H-pyrazol-5-yl) -5-nitro-2-[(E) -2-phenylvinyl] pyrimidine-4,6-diamine to N, N′-bis (3-methyl- 1H-pyrazol-5-yl) -2-[(E) -2-phenylvinyl] pyrimidine-4,5,6-triamine was obtained in 43% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.86 (br, 2H), 8.41 (br, 2H), 7.2 to 7.8 (m, 6H), 7.0 to 7. 1 (br, 1H), 6.5 (br, 1H), 2.11 (s, 6H). MS (m / z) 388 (M + l).

(Example 12)

N- (3-Methyl-1H-pyrazol-5-yl) -6- (morpholin-4-yl) -2-[(E) -2-phenylvinyl] pyrimidine-4,5-diamine N of Example 6 -(3-Methyl-1H-pyrazol-5-yl) -5-nitro-6- (morpholin-4-yl) -2-[(E) -2-phenylvinyl] pyrimidin-4-amine to N- ( 3-methyl-1H-pyrazol-5-yl) -6- (morpholin-4-yl) -2-[(E) -2-phenylvinyl] pyrimidine-4,5-diamine was recovered by 21% after preparative hplc. Obtained in yield. ¹ H NMR (400 MHz, CDCl ₃ ): δ 11.35 (br, 1H), 7.58 (m, 2H), 7.42 (m, 4H), 6.74 (d, 1H, J = 16 Hz) 5.82 (s, 1H), 3.67 (m, 4H), 3.27 (m, 4H), 2.17 (s, 3H). MS (m / z) 378 (M + l).

(Example 13)

N- (3-Methyl-1H-pyrazol-5-yl) -6- (piperazin-1-yl) -2-[(E) -2-phenylvinyl] pyrimidine-4,5-diamine N of Example 7 -(3-Methyl-1H-pyrazol-5-yl) -5-nitro-6- (piperazin-1-yl) -2-[(E) -2-phenylvinyl] pyrimidin-4-amine to N- ( 3-methyl-1H-pyrazol-5-yl) -6- (piperazin-1-yl) -2-[(E) -2-phenylvinyl] pyrimidine-4,5-diamine was separated by 17% after preparative hplc. Obtained in yield. ¹ H NMR (400 MHz, CDCl ₃ ): δ 11.3 (br, 1H), 7.31 to 7.63 (m, 6H), 6.82 (d, 1H, J = 16 Hz), 5.85 ( s, 1H), 3.28 (m, 4H), 2.22 (s, 3H), 1.65 (m, 4H). MS (m / z) 377 (M + l).

(Example 14)

N- (3-Methyl-1H-pyrazol-5-yl) -6- (piperidin-1-yl) -2-[(E) -2-phenylvinyl] pyrimidine-4,5-diamine N of Example 8 -(3-Methyl-1H-pyrazol-5-yl) -5-nitro-6- (piperidin-1-yl) -2-[(E) -2-phenylvinyl] piperidin-4-amine to N- ( 3-Methyl-1H-pyrazol-5-yl) -6- (piperidin-1-yl) -2-[(E) -2-phenylvinyl] pyrimidine-4,5-diamine was obtained in 18% yield. It was. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.73 (d, 1H, J = 16 Hz), 7.62 (d, 2H, J = 7.2 Hz), 7.39 (t, 2H, J = 7) .2 Hz), 7.32 (m, 1 H), 7.09 (d, 1 H, J = 16 Hz), 6.3 (s, 1 H), 3.29 (br, 2 H), 3.22 (br, 4H), 2.36 (s, 3H), 1.4-1.9 (m, 6H). MS (m / z) 376 (M + l).

(Example 15)

N- (3-Methyl-1H-pyrazol-5-yl) -6- (pyrrolidin-1-yl) -2-[(E) -2-phenylvinyl] pyrimidine-4,5-diamine N of Example 9 -(3-Methyl-1H-pyrazol-5-yl) -5-nitro-6- (pyrrolidin-1-yl) -2-[(E) -2-phenylvinyl] pyrimidin-4-amine to N- ( 3-methyl-1H-pyrazol-5-yl) -6- (pyrrolidin-1-yl) -2-[(E) -2-phenylvinyl] pyrimidine-4,5-diamine was obtained in 20% yield. It was. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.88 (br, 1H), 7.71 (d, 1H, J = 16 Hz), 7.59 (d, 2H, J = 7.2 Hz), 7. 39 (t, 2H, J = 7.2 Hz), 7.29 (m, 1H), 7.00 (d, 1H, J = 16 Hz), 5.95 (s, 1H), 3.73 (m, 4H), 2.67 (br, 2H), 2.30 (s, 3H), 1.97 (m, 4H). MS (m / z) 362 (M + l).

(Example 16)

Ethyl 2-chloro-6-[(3-methyl-1H-pyrazol-5-yl) amino] -5-nitropyrimidine-4-carboxylate Commercial ethyl in anhydrous 1,4-dioxane (5 mL) at room temperature. 2,6-Dichloro-5-nitripyrididine-4-carboxylate (Matrix Scientific, 1.00 g, 3.76 mmol, 1.0 eq) and 2,6-lutidine (0.65 mL, 5.60 mmol, 1.5 eq) ) Was added dropwise a solution of 5-methyl-3-aminopyrazole (0.38 g, 3.95 mmol, 1.05 eq) in anhydrous 1,4-dioxane (5 mL). The solution was stirred at room temperature for 30 minutes, diluted with ethyl acetate (100 mL), washed with 1N hydrochloric acid (50 mL × 3) and saturated brine (50 mL × 1), dried over Na ₂ SO ₄ , concentrated, Drying gave a light brown solid as Example 16 (1.16 g, 95%). R _f: 0.55 (60% ethyl acetate / hexanes); MS m / z 327, calcd _{327 (C 11 H 11 ClN 6} O 4 + H).

(Example 17)

Ethyl 6-[(3-methyl-1H-pyrazol-5-yl) amino] -5-nitro-2-[(E) -2-phenylvinyl] pyrimidine-4-carboxylate Example 16 (100 mg, 0. 31 mmol, 1.0 eq), anhydrous potassium carbonate (64 mg, 0.46 mmol, 1.5 eq), trans-2-phenylvinylboronic acid (69 mg, 0.46 mmol, 1.5 eq), and tetrakis (triphenyl) To a glass vessel containing phosphine) palladium (0) (18 mg, 0.015 mmol, 0.05 eq), anhydrous toluene (3 mL) was added under a nitrogen atmosphere. The suspension was degassed by bubbling with nitrogen for 2-3 minutes. The suspension was then heated at 70 ° C. with rapid stirring for 8 hours, cooled to room temperature, diluted with water (50 mL) and extracted with dichloromethane (50 mL × 3). The combined extracts were concentrated under reduced pressure. The residue was purified on a silica gel flash column with 0-50% ethyl acetate / hexanes to give Example 17 as an orange solid (62 mg, 51%). R _f: 0.40 (60% ethyl acetate / hexanes); MS m / z 395, calcd _{395 (C 19 H 18 N 6} O 4 + H).

(Example 18)

Ethyl 5-amino-6-[(3-methyl-1H-pyrazol-5-yl) amino] -2-[(E) -2-phenylvinyl] pyrimidine-4-carboxylate dimethyl sulfoxide (5 mL) and acetonitrile ( To a solution of Example 16 (0.40 g, 1.02 mmol, 1 eq) in 20 mL) was added zinc powder (0.66 g, 10.09 mmol, 10 eq) followed by ammonium formate (0.63 g, 10 eq). 0.000 mmol, 10 equivalents) was added. This suspension was stirred at room temperature for 30 minutes. The solid was filtered off through a celite pad and the filtrate was concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography using 5% methanol / chloroform to give Example 18 as a yellow solid ( 70 mg, 19%). R _f : 0.55 (10% methanol / dichloromethane); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.19 (br s, 1 H), 9.60 (br s, 1 H), 7.63 ( d, J = 7.5 Hz, 12H), 7.53 (d, J = 15.9 Hz, 1H), 7.35-7.45 (m, 2H), 7.26-7.34 (m, 1H) ), 7.07 (d, J = 16.0 Hz, 1H), 7.04 (br s, 2H), 6.75 (s, 1H), 4.38 (q, J = 7.8 Hz, 2H) , 2.32 (s, 3H), 1.34 (t, J = 7.8Hz, 3H); MS m / z 365, _{calc: 365 (C 19 H 20 N} 6 O 2 + H).

  Examples 19 to 23 were prepared in the same way as Example 17 starting from Example 16 by replacing trans-2-phenylvinylboronic acid with the appropriate vinylboronic acid in the synthetic route.

(Example 19)

Ethyl 5-amino-2-[(E) -2- (4-chlorophenyl) vinyl] -6-[(3-methyl-1H-pyrazol-5-yl) amino] pyrimidine-4-carboxylate trans-2- Replacing phenylvinylboronic acid with trans-2- (4-chlorophenyl) vinylboronic acid gave a pale yellow solid (14 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.12 (br s, 1H), 9.52 (s, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.49 ( d, J = 16.0 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.09 (d, J = 16.0 Hz, 1H), 7.04 (s, 2H), 6.75 (s, 1H), 4.34 (q, J = 7.0 Hz, 2H), 2.32 (s, 3H), 1.34 (t, J = 7.0 Hz, 3H); MS m / z 399, _{calc: 399 (C 19 H 19 ClN} 6 O 2 + H).

(Example 20)

Ethyl 5-amino-6-[(3-methyl-1H-pyrazol-5-yl) amino] -2-{(E) -2- [4- (trifluoromethyl) phenyl] vinyl} pyrimidine-4-carboxy Replacing the trans-2-phenylvinylboronic acid with trans-2- (4- (trifluoromethyl) phenyl) vinylboronic acid gave a pale yellow solid (60 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.20 (br s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H) ), 7.66 (d, J = 16.0 Hz, 1H), 7.41-7.37 (m, 3H), 6.76 (s, 1H), 4.40 (q, J = 6.9 Hz) , 2H), 2.34 (s, 3H), 1.37 (t, J = 6.9Hz, 3H); MS m / z 433, _{calc: 433 (C 20 H 19 F} 3 N 6 O 2 + H ).

(Example 21)

Ethyl 5-amino-2-[(E) -2- (4-methylphenyl) vinyl] -6-[(3-methyl-1H-pyrazol-5-yl) amino] pyrimidine-4-carboxylate trans-2 -A light yellow solid (22 mg) was obtained by replacing phenylvinylboronic acid with trans-2- (4-methylphenyl) vinylboronic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.13 (br s, 1H), 9.49 (s, 1H), 7.55 to 7.48 (m, 3H), 7.21 (d, J = 7.9 Hz, 2H), 7.02 to 7.00 (m, 3H), 6.78 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.33 ( s, 6H), 1.34 (t , J = 7.1Hz, 3H); MS m / z 379, _{calc: 379 (C 20 H 22 N} 6 O 2 + H).

(Example 22)

Ethyl 5-amino-2-[(E) -2- (3-fluorophenyl) vinyl] -6-[(3-methyl-1H-pyrazol-5-yl) amino] pyrimidine-4-carboxylate trans-2 -A light yellow solid (13 mg) was obtained by replacing phenylvinylboronic acid with trans-2- (3-fluorophenyl) vinylboronic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.11 (br s, 1H), 9.51 (s, 1H), 7.56 to 7.38 (m, 4H), 7.14 to 7. 04 (m, 4H), 6.76 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 2.31 (s, 3H), 1.32 (t, J = 7. 1Hz, 3H); MS m / z 383, _{calc: 383 (C 19 H 19 FN} 6 O 2 + H).

(Example 23)

Ethyl 5-amino-2-[(E) -2- (4-methoxyphenyl) vinyl] -6-[(3-methyl-1H-pyrazol-5-yl) amino] pyrimidine-4-carboxylate trans-2 -A pale yellow solid (76 mg) was obtained by replacing phenylvinylboronic acid with trans-2- (4-methoxyphenyl) vinylboronic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.70 (d, J = 15.7 Hz, 1H), 7.59 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 15.7 Hz, 1H), 7.02 (d, J = 8.7 Hz, 2H), 6.48 (brs, 4H), 4.42 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 2.32 ( s, 3H), 1.35 (t, J = 7.1Hz, 3H); MS m / z 395, _{calc: 395 (C 20 H 22 N} 6 O 3 + H ).

(Example 24)

1-methylpiperidin-4-yl 5-amino-6-[(3-methyl-1H-pyrazol-5-yl) amino] -2-[(E) -2-phenylvinyl] pyrimidine-4-carboxylate A mixture of Example 18 (4.5 g, 12.3 mmol, 1 eq) and 4-hydroxy-N-methylpiperidine (40 mL) was slowly added to titanium isopropoxide (1 mL). The reaction was heated at reflux overnight. Excess alcohol was distilled off and the resulting solid was purified by silica gel column chromatography using 3% methanol / dichloromethane to give Example 24 as a yellow solid (1.55 g, 29%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.11 (s, 1H), 9.49 (s, 1H), 7.64 to 7.62 (m, 2H), 7.53 (d, J = 16.0 Hz, 1H), 7.40-7.27 (m, 3H), 7.05-6.98 (m, 3H), 6.76 (s, 1H), 4.88 (m, 1H) ), 2.73 to 2.49 (m, 2H), 2.30 (s, 3H), 2.15 (m, 5H), 1.97 to 1.93 (m, 2H), 1.77 to 1.69 (m, 2H); MS m / z 434, _{calc: 434 (C 23 H 27 N} 7 O 2 + H).

(Example 25)

N- (2-morpholin-4-ylethyl) -5-amino-6-[(3-methyl-1H-pyrazol-5-yl) amino] -2-[(E) -2-phenylvinyl] pyrimidine-4 Carboxamide At 0 ° C., to a mixture of Example 18 (2.5 g, 6.9 mmol, 1 eq) and 2-morpholin-4-ylethylamine (1.8 g, 13.7 mmol, 2 eq) in anhydrous dichloromethane Trimethylaluminum (28 mL, 54.8 mmol, 8 equivalents) was added dropwise over about 1 hour. The reaction was brought to room temperature and stirred for an additional 4 hours. The reaction was carefully quenched with 1.5N hydrochloric acid (20 mL). The resulting solid was collected and purified by silica gel column chromatography using 4% methanol / dichloromethane to give Example 25 as a yellow solid (1.1 g, 36%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.08 (s, 1H), 9.34 (s, 1H), 8.75 (s, 1H), 7.64 to 7.60 (m, 3H) ), 7.42-7.39 (m, 2H), 7.30 (m, 1H), 7.14 (s, 2H), 7.02 (d, J = 16.0 Hz, 1H), 6. 77 (s, 1H), 3.61 to 3.59 (m, 4H), 3.41 to 3.38 (m, 2H), 2.53 to 2.49 (m, 6H), 2.29 ( s, 3H); MS m / z 449, _{calc: 449 (C 23 H 28 N} 8 O 2 + H).

(Example 26)

Methyl 6-[(3-Methyl-1H-pyrazol-5-yl) amino] -2-[(E) -2-phenylvinyl] pyrimidine-4-carboxylate Reaction pathway used to produce Example 17 Example 26 was obtained as a pale yellow solid (30 mg) by replacing ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate with commercially available methyl 2,4-dichloropyrimidine-6-carboxylate in . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.30 (br s, 1H), 7.85 (d, J = 16.0 Hz, 1H), 7.65 to 7.75 (m, 2H), 7.33-7.48 (m, 4H), 7.19 (d, J = 16.0 Hz, 1H), 6.40 (br s, 1H), 3.89 (s, 3H), 2.27 (s, 3H); MS m / z 336, _{calc: 336 (C 18 H 17 N} 5 O 2 + H).

(Example 27)

4,6-Dichloro-2- (methylsulfonyl) pyrimidine Commercially available 4,6-dichloro-2-methylthiopyrimidine (Aldrich, 21.0 g, 107.0 mmol, 1 equivalent) was dissolved in dichloromethane and cooled in an ice bath. . 3-Chlorobenzoyl peroxide (60.0 g, 77 wt%, 268.0 mmol, 2.5 eq) was added in small portions. The resulting white suspension was stirred at room temperature for 4 hours, 1M sodium thiosulfate / saturated sodium bicarbonate (1: 1, volume / volume, 200 mL × 3), and saturated sodium bicarbonate (100 mL × 3), and Washed with saturated brine (100 mL × 1). The organic solution was dried under reduced pressure and concentrated. After drying under high vacuum overnight, Example 27 was obtained as a white solid (22.0 g, 91%). R _f: 0.20 (20% ethyl acetate / hexanes); MS m / z 227, calcd _{227 (C 5 H 4 Cl 2} N 2 O 2 S + H).

(Example 28)

4,6-Dichloro-2- (phenylethynyl) pyrimidine Example 27 (4.54 g, 20.00 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (50 mL) and cooled to −20 ° C. Phenylacetylenylmagnesium bromide (22.00 mL, 1.0 M in tetrahydrofuran, 22.00 mmol, 1.1 eq) was added dropwise with vigorous stirring. The solution was stirred overnight while returning from −20 ° C. to room temperature, diluted with ethyl acetate (300 mL), and added to 1N hydrochloric acid (200 mL). The mixture was stirred vigorously for 5 minutes. The organic layer was collected and the aqueous layer was extracted with additional ethyl acetate (100 mL × 2). The combined organic solution was dried over Na ₂ SO ₄ , concentrated under reduced pressure, and dried under high vacuum overnight to give Example 28 as an off-white solid (5.00 g, quantitative). R _f: 0.75 (20% ethyl acetate / hexanes); MS m / z 249, calcd _{249 (C 12 H 6 N 2} Cl 2 + H).

(Example 29)

6-Chloro-N- (3-methyl-1H-pyrazol-5-yl) -2- (phenylethynyl) pyrimidin-4-amine Example 28 (5.00 g, 20.00 mmol, 1 eq) was converted to anhydrous dimethylacetamide. Dissolved in (20 mL). 5-methyl-2-aminopyrazole (2.14 g, 22.00 mmol, 1.1 eq), sodium iodide (3.60 g, 24.00 mmol, 1.2 eq), and diisopropylethylamine (4.18 mL, 24 0.000 mmol, 1.2 eq) was added. The solution was heated at 90 ° C. overnight, cooled to room temperature, diluted with ethyl acetate (200 mL), washed with saturated sodium bicarbonate (200 mL × 3), dried and concentrated under reduced pressure. The resulting crude product was purified using silica gel flash chromatography with 0-4% methanol / dichloromethane to give Example 29 as a yellow solid (5.51 g, 89%). R _f : 0.40 (5% methanol / dichloromethane); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.13 (br s, 1 H), 10.39 (s, 1 H), 7.63 (d , J = 7.5 Hz, 2H), 7.40-7.60 (m, 4H), 5.95 (br s, 1H), 2.22 (s, 3H); MS m / z 310, calculated value _{: 310 (C 16 H 12 ClN} 5 + H).

(Example 30)

6- (4-Methylpiperazin-1-yl) -N- (3-methyl-1H-pyrazol-5-yl) -2- (phenylethynyl) pyrimidin-4-amine Example 29 (2.80 g, 9. 04 mmol, 1 equivalent) was dissolved in anhydrous 1,4-dioxane (10 mL). N-methylpiperazine (1.10 mL, 9.92 mmol, 1.1 eq), 4-dimethylaminopyridine (0.055 g, 0.45 mmol, 0.05 eq), and diisopropylethylamine (1.89 mL, 10.85 mmol) 1.2 equivalents) was added. The solution was stirred at 100 ° C. for 2 hours, cooled to room temperature and concentrated under reduced pressure. The residue was purified using silica gel flash chromatography with 0-10% methanol / dichloromethane to give Example 30 as a pale yellow solid (3.00 g, 89%). R _f : 0.10 (5% methanol / dichloromethane); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.90 (br s, 1 H), 9.43 (s, 1 H), 7.57 (d , J = 7.5 Hz, 2H), 7.40-7.50 (m, 3H), 6.80 (brs, 1H), 5.82 (s, 1H), 3.51 (brs, 4H) ), 2.43 (br s, 4H), 2.27 (s, 3H), 2.18 (s, 3H); MS m / z 374, calcd: 374 (C ₂₁ H ₂₃ N ₇ + H).

(Example 31)

6- (4-Methylpiperazin-1-yl) -N- (3-methyl-1H-pyrazol-5-yl) -2-[(E) -2-phenylvinyl] pyrimidin-4-amine Example 30 ( 2.54 g, 6.80 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (50 mL) and cooled using an ice-water bath. Lithium aluminum hydride (5.61 mL, 1.0 M in tetrahydrofuran, 5.61 mmol, 0.83 equiv) was added dropwise with rapid stirring. The solution was stirred for 12 hours while returning from 0 ° C. to room temperature. The reaction was cooled to 0 ° C. and slowly quenched with methanol (5 mL). Saturated potassium sodium tartrate (500 mL) was added to the reaction mixture. The resulting suspension was stirred rapidly at room temperature until a clear solution was obtained. This solution was then extracted with ethyl acetate (100 mL × 5). The combined extracts were dried and concentrated under reduced pressure. Silica gel flash chromatography using 0-8% methanol / dichloromethane gave Example 31 as an off-white solid (1.55 g, 61%). R _f : 0.30 (10% methanol / dichloromethane); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.80 (br s, 1 H), 9.08 (s, 1 H), 7.72 (d , J = 15.9 Hz, 1H), 7.63 (d, J = 7.2 Hz, 2H), 7.28-7.45 (m, 3H), 6.92 (d, J = 15.9 Hz, 1H), 6.62 (brs, 1H), 5.95 (s, 1H), 3.56 (brs, 4H), 2.45 (brs, 4H), 2.26 (s, 3H) , 2.20 (s, 3H); MS m / z 376, _{calc: 376 (C 21 H 25 N} 7 + H).

  Example 31 was also made according to Scheme 6 as shown below.

(Example 32)

6- (4-Methylpiperazin-1-yl) -N- (3-methyl-1H-pyrazol-5-yl) -2-[(Z) -2-phenylvinyl] pyrimidin-4-amine Example 30 ( 38 mg, 0.10 mmol) was dissolved in ethyl acetate / methanol (2: 1, volume / volume, 1.5 mL). Quinoline (0.04 mL) and Lindlar catalyst (20 mg) were added. The suspension was degassed with hydrogen and rapidly stirred overnight under a hydrogen atmosphere (1 atm). The catalyst was removed by filtration through a small celite pad. The filtrate was concentrated and the residue was purified using silica gel preparative thin layer chromatography with 10% methanol / dichloromethane to give Example 32 as an off-white solid (32 mg, 85%). R _f : 0.45 (10% methanol / dichloromethane); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.78 (br s, 1 H), 9.19 (s, 1 H), 7.38 (d , J = 7.2 Hz, 2H), 7.15-7.30 (m, 3H), 6.77 (d, J = 12.5 Hz, 1H), 6.50 (brs, 1H), 6. 36 (d, J = 12.5 Hz, 1H), 5.74 (s, 1H), 3.35 to 3.50 (m, 4H), 2.65 to 2.80 (m, 4H), 2. 56 (s, 3H), 2.13 (s, 3H); LRMS m / z 376, _{calc: 376 (C 21 H 25 N} 7 + H).

(Example 33)

4,6-dichloro-2-[(E) -2-phenylvinyl] pyrimidine This was rapidly stirred into a solution of Rieke Mg (4.81 g, 200 mmol, 1.5 eq) in tetrahydrofuran under a nitrogen atmosphere. While, a solution of β-bromostyrene (mixture of cis and trans, 29.00 g, 160 mmol, 1.2 eq) in tetrahydrofuran was added at a rate such that the temperature of the reaction was kept between 40-60 ° C. throughout the addition process. It was dripped at. After the addition, the resulting dark red solution was stirred at room temperature for 30 minutes and passed through a double-ended needle into a cooled (−20 ° C.) tetrahydrofuran solution of Example 27 (30.00 g, 132 mmol, 1 equivalent) within 45 minutes. Slowly added. The reaction was stirred from -20 ° C to room temperature for 4 hours, cooled to -20 ° C and quenched by the dropwise addition of 1N hydrochloric acid (200 mL). The mixture was concentrated under reduced pressure at room temperature and extracted with ethyl acetate (500 mL). The ethyl acetate layer was separated, washed with 1N hydrochloric acid (200 mL × 3), dried and concentrated under reduced pressure. The crude product was purified using silica gel flash chromatography with 0-2% ethyl acetate / hexanes to give Example 33 as a pale yellow solid (14.20 g, -9: 1 trans / cis, 43%). It was. R _f: 0.60 (5% ethyl acetate / hexanes); MS m / z 251, calcd _{251 (C 12 H 8 Cl 2} N 2 + H).

  Example 33 was also synthesized according to Scheme 6 as shown below.

(Example 34)

6-chloro-N- (3-methyl-1H-pyrazol-5-yl) -2-[(E) -2-phenylvinyl] pyrimidin-4-amine Example 33 (14.20 g, 56.55 mmol, 1 Equivalent) was dissolved in anhydrous dimethylacetamide (100 mL). 5-Methyl-3-aminopyrazole (6.60 g, 68.00 mmol, 1.2 equiv), sodium iodide (12.70 g, 84.73 mmol, 1.5 equiv), and diisopropylethylamine (14.76 mL, 84 .73 mmol, 1.5 eq) was added. The solution was stirred at 90 ° C. for 12 hours, cooled to room temperature, diluted with ethyl acetate (500 mL), water (500 mL × 1), saturated sodium bicarbonate (200 mL × 3), and saturated brine (100 mL × 1). ), Dried and concentrated under reduced pressure. The resulting semi-solid was suspended in a minimum amount of dichloromethane (15 mL) with rapid stirring, and the fine precipitate was collected by filtration and washed with dichloromethane / hexane (1: 1, volume / volume, 10 mL × 4). Washed and dried under high vacuum overnight to give Example 34 as an off-white solid (8.75 g, 50%, trans only). R _f : 0.75 (10% methanol / dichloromethane); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.20 (s, 1 H), 10.16 (s, 1 H), 7.83 (d, J = 12.0 Hz, 1H), 7.73 (d, J = 5.1 Hz, 2H), 7.36-7.48 (m, 4H), 7.07 (d, J = 12.0 Hz, 1H) ), 5.78 (s, 1H) , 2.24 (s, 3H); MS m / z 312, _{calc: 312 (C 16 H 14 ClN} 5 + H).

  Example 34 was also synthesized according to Scheme 6 as shown below.

(Example 35)

6- (4-Methylpiperazin-1-yl) -N- (3-methyl-1H-pyrazol-5-yl) -2-[(E) -2-phenylvinyl] pyrimidin-4-amine Example 34 ( 7.79 g, 25.00 mmol, 1 eq) was dissolved in 1,4-dioxane (15 mL). N-methylpiperazine (4.16 mL, 37.50 mmol, 1.5 eq), 4-dimethylaminopyridine (0.15 g, 1.25 mmol, 0.05 eq), and diisopropylethylamine (6.97 mL, 40.00 mmol) 1.6 eq.) Was added. The solution was stirred at 100 ° C. for 48 hours, cooled to room temperature and concentrated under reduced pressure. The residue was purified using silica gel flash chromatography with 0-8% methanol / dichloromethane to give Example 31 as a pale yellow solid (3.56 g, 38%). Example 35 was also synthesized according to Scheme 6 shown below. All analytical data were the same as in Example 31 prepared by the alternative route described.

(Example 36)

Methyl 4-[(E) -2- (3,5-dihydroxy-4-nitrophenyl) vinyl] benzoate Example 1 (2 g, 11.69 mmol) was added to 4-formylbenzoic acid methyl ester (7.69 g, 46.76 mmol) was added followed by piperidine (10 mL, 93.52 mmol). The reaction mixture was heated at 90 ° C. for 4 hours. The reaction mixture was then cooled to room temperature and methanol (10 mL) was added followed by diethyl ether (100 mL). The resulting solid was filtered and washed with 5% hydrochloric acid to give Example 36 (2.0 g). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.3 (br, 1H), 8.0 to 8.2 (m, 3H), 7.4 (d, 2H, J = 8 Hz), 6. 9 (d, 1H, J = 16.4 Hz), 3.88 (s, 3H).

(Example 36A)

Methyl 4-[(E) -2- (3,5-dichloro-4-nitrophenyl) vinyl] benzoate Example 36 (6 g, 19.8 mmol) was treated with phosphorus oxychloride (21 mL, 229 mmol) and then Diethylaniline (9.5 mL, 59.6 mmol) was added dropwise. The reaction mixture was heated at 80 ° C. overnight. The reaction mixture was then poured into crushed ice and the resulting solid was collected and dried. This compound was then purified by column chromatography. Example 36A (1.7 g) was obtained using 10% ethyl acetate: hexane as the eluent. ¹ H NMR (400 MHz, CDCl 3): δ 8.0 to 8.2 (m, 3H), 7.70 (m, 2H), 7.47 (d, 2H, J = 8 Hz), 7.22 (d , 1H, J = 16.4 Hz), 3.95 (s, 3H).

(Example 37)

Methyl 4-((E) -2- {4-chloro-6-[(3-methyl-1H-pyrazol-5-yl) amino] -5-nitropyrimidin-2-yl} vinyl) benzoate tetrahydrofuran (30 mL To a solution of Example 36A (1.55 g, 4.39 mmol) in) was added triethylamine (1.1 mL, 7.9 mmol) at room temperature (30 ° C.) under a nitrogen atmosphere. After 15 minutes, 5-amino-2-methyl-pyrazole (426 mg, 4.39 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction mixture. After 5 hours, the reaction mixture was evaporated to dryness. The obtained solid was pulverized with ethyl acetate and hexane to obtain Example 37 (1.8 g). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.1 (br, 1H), 9.75 (br, 1H), 8.08 (m, 3H), 7.69 (d, 1H, J = 8.4 Hz), 7.13 (d, 1 H, J = 16 Hz), 6.66 (s, 1 H), 3.94 (s, 3 H), 2.17 (s, 3 H). MS (m / z) 415 (M + l).

(Example 38)

Methyl 4-((E) -2- {4- (4-methylpiperazin-1-yl) -6-[(3-methyl-1H-pyrazol-5-yl) amino] -5-nitropyrimidine-2- Yl} vinyl) benzoate To a solution of Example 37 (2.0 g, 4.83 mmol) in tetrahydrofuran (30 mL) was added triethylamine (1.0 mL, 7.3 mmol) at room temperature (30 ° C.) under a nitrogen atmosphere. did. After 15 minutes, N-methylpiperazine (483 mg, 4.83 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction mixture. After 0.5 hours, the reaction mixture was evaporated to dryness. The obtained solid was triturated with ethyl acetate and hexane to give Example 38 (2.2 g). 500 mg of the crude compound was purified by preparative HPLC to give pure Example 38 (150 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.53 (br, 1H), 10.00 (br, 1H), 7.9 to 8.1 (m, 5H), 7.4 (m, 1H, J = 16 Hz), 6.75 (s, 1H), 3.88 (s, 3H), 3.0 to 3.2 (m, 4H), 2.9 (m, 4H), 2.3 (S, 3H), 2.09 (s, 3H). MS (m / z) 479 (M + l).

(Example 39)

Methyl 4-((E) -2- {5-amino-4- (4-methylpiperazin-1-yl) -6-[(3-methyl-1H-pyrazol-5-yl) amino] -pyrimidine-2 -Il} vinyl) benzoate Tin (II) chloride dihydrate (1.0 g, 4.4 mmol) was dissolved in concentrated hydrochloric acid (1 mL, 9.04 mmol). The reaction mixture was stirred for 10 minutes and then cooled to <10 ° C. Example 38 (250 mg, 0.52 mmol) in methanol (20 mL) was added dropwise to the reaction mixture. Cooling was stopped and the reaction was stirred overnight. The reaction mixture was evaporated to 1/3 volume and then diluted with 40 mL of ethyl acetate. A solution of 1N NaOH (20 mL) was added to the reaction mixture. The organic layer was then separated, dried and evaporated under reduced pressure. The resulting crude solid was then purified by preparative HPLC to give 30 mg of Example 39. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.89 (br, 1H), 8.93 (br, 1H), 7.96 (d, 2H, J = 8 Hz), 7.77 (d, 2H) , J = 8 Hz), 7.57 (d, 1H, J = 16 Hz), 7.24 (br, 1H), 7.17 (d, 1H, J = 16 Hz), 7.11 (br, 1H), 6.99 (br, 1H), 6.58 (s, 1H), 3.88 (s, 3H), 3.1-3.8 (m, 8H), 2.88 (s, 3H), 2 .31 (s, 3H). MS (m / z) 449 (M + l).

(Example 31 according to Scheme 6)

6- (4-Methylpiperazin-1-yl) -N- (3-methyl-1H-pyrazol-5-yl) -2-[(E) -2-phenylvinyl] pyrimidin-4-amine according to Scheme 6 Synthesis According to the general description described above for Scheme 6, commercially available cinnamonitrile (70 g) was dissolved in absolute toluene (1.19 L) and absolute ethanol (287 ml, 0.91 mol, 9 eq). The resulting clear solution is cooled to −5 ° C. and dry HCl gas is gently bubbled in for 2 hours, then the reaction is sealed and stirred for 15 hours at 0 ° C. -Ethyl imidate HCl salt (100 g) was obtained. ¹ H-NMR (200 MHz, DMSO-D ₆ ): 11.63 (2H, bs), 7.98 (1H, d, J = 16.2 Hz), 7.73-7.32 (5H, m), 7.01 (1H, d, J = 16.2 Hz), 4.46 (2H, q), 1.41 (3H, t, J = 5.2 Hz).

O-ethyl imidate HCl salt (100 g) in ethanol (500 ml) was cooled to 0 ° C. and a solution of anhydrous ammonia (204 ml, 7N, 0.30 mol) in methanol was added. The mixture was stirred at room temperature for 12 hours. This mixture was worked up to give Intermediate-1 (80 g, 89%). ¹ H-NMR (200 MHz, DMSO-D ₆ ): 9.32 (2H, bs), 8.84 (2H, bs), 7.97 (1H, d, J = 16.2 Hz), 7.62 to 7.44 (5H, m), 6.81 (1H, d, J = 16.2 Hz); M + 147 (100%, m / z).

To intermediate-1 (80 g) in methanol (80 ml) was added dimethyl malonate (80 ml, 1.1 eq) at room temperature. The mixture was cooled to 0 ° C. and NaOCH ₃ (44 g, 4.4 eq) was added slowly over 10 minutes. The pale yellowish white solution was heated to 90 ° C. and refluxed for 4 hours. Post-treatment gave Intermediate-2 (70 g, 60%). ¹ H-NMR (200 MHz, DMSO-D ₆ ): 11.62 (2H, bs), 7.87 (1H, d, J = 16.2 Hz), 7.60-7.41 (5H, m), 6.85 (1H, d, J = 16.2 Hz), 5.22 (1H, s); M + 215 (100%, m / z).

Intermediate-2 (70 g) was added slowly in 600 ml portions of POCl ₃ . The mixture was stirred at 100 ° C. for 4-6 hours. The reaction mixture was concentrated to dryness at 60 ° C. under reduced pressure. Post-treatment gave Intermediate-3 (70 g, 85%). ¹ H-NMR (200 MHz, DMSO-D ₆ ): 7.96 (1H, d, J = 16.2 Hz), 7.80 (2H, m), 7.45 to 7.21 (5H, m); M + 250.9, 252.9 (100%, m / z).

To a solution of intermediate-3 (70 g, 0.2278 mole) in anhydrous DMA (400 ml) was added 5-methyl-3-aminopyrazole (32.50 g, 0.334 mol), NaI (62.33 g, 0.418 mole). , And DIPEA (54 g, 1.48 mol) were added and the mixture was stirred at 90 ° C. for 12 hours. Work-up and chromatographic purification gave compound-4 (50 g, 57%). ¹ H-NMR (200 MHz, DMSO-D ₆ ): 12.12 (1H, s), 10.18 (1H, s), 7.83 (1H, d, J = 16.2 Hz), 7.71 ( 3H, m), 7.45 to 7.33 (3H, m), 7.12 (1H, d, J = 16.2 Hz), 6.22 (1H, bs), 2.21 (3H, s) M + 312 (100%, m / z).

Intermediate-4 (50 g) was dissolved in N-methylpiperazine (150 ml) and heated at 110 ° C. for 1 hour. The desired example (25 g, 41.4%) was obtained by workup and crystallization. ¹ H-NMR (200 MHz, DMSO-D ₆ ): 11.92 (1H, s), 9.18 (1H, s), 7.76 (1H, d, J = 16.2 Hz), 7.62 ( 2H, m), 7.41-7.35 (3H, m), 6.91 (1H, d, J = 16.2 Hz), 6.61 (1H, bs), 6.01 (1H, bs) 3.57 (4H, m), 2.41 (4H, m), 2.22 (3H, s), 2.20 (3H, s); HPLC (98.1% purity, RT: 24.36). Min, gradient: 0.1% TFA / acetonitrile and 0.1% TFA / water, Hypersil BDS C-18, 4.6 × 150 mm, 5.0 u).

(Example 49)

2- (4-Chlorostyryl) -N- (5-methyl-1H-pyrazol-3-yl) -6- (4-methylpiperazin-1-yl) pyrimidin-4-amine Example 49 is a suitable starting material. Synthesized according to Scheme 6 according to the general scheme provided above, using the materials 3- (4-chlorophenyl) acrylonitrile, 5-methyl-1H-pyrazol-3-amine, and 1-methylpiperazine. The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

(Example 50)

2- (3,5-Dimethoxystyryl) -N- (5-methyl-1H-pyrazol-3-yl) -6- (4-methylpiperazin-1-yl) pyrimidin-4-amine Using the starting materials 3- (3,5-dimethoxyphenyl) acrylonitrile, 5-methyl-1H-pyrazol-3-amine, and 1-methylpiperazine, according to Scheme 6 following the general scheme provided above Synthesized. The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

(Example 60)

2-((E) -2- (furan-2-yl) vinyl) -N- (5-methyl-1H-pyrazol-3-yl) -6- (4-methylpiperazin-1-yl) pyrimidine-4 -Amine Example 60 was provided above using the appropriate starting materials 3- (furan-2-yl) acrylonitrile, 5-methyl-1H-pyrazol-3-amine, and 1-methylpiperazine. Synthesized according to Scheme 6 following the general scheme. The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

(Example 64)

N- (5-Methyl-1H-pyrazol-3-yl) -6-morpholino-2-styrylpyrimidin-4-amine Synthesized according to Scheme 6 according to the general scheme provided above, using -3-amine and morpholine. The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

Example 66

N ⁴ - (2-(dimethylamino) ethyl) ^-N 6 - (5-methyl -1H- pyrazole-3 -yl) -2-styryl 4,6-diamine Example 66, with appropriate starting materials Synthesized according to Scheme 6 following the general scheme provided above, using certain cinnamonitriles, 5-methyl-1H-pyrazol-3-amine, and N ¹ , N ¹ -dimethylethane-1,2-diamine. . The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

(Example 67)

N- (5-Methyl-1H-pyrazol-3-yl) -6- (piperidin-1-yl) -2-styrylpyrimidin-4-amine Example 67 is a suitable starting material, cinnamonitrile, 5 Synthesized according to Scheme 6 following the general scheme provided above using -methyl-1H-pyrazol-3-amine and piperidine. The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

(Example 69)

6- (2- (Dimethylamino) ethoxy) -N- (5-methyl-1H-pyrazol-3-yl) -2-styrylpyrimidin-4-amine Example 69 is a suitable starting material, cinnamonitrile. , 5-methyl-1H-pyrazol-3-amine, and (2-dimethyl) aminoethanol were synthesized according to Scheme 6 following the general scheme provided above. The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

(Example 71)

N- (5-Methyl-1H-pyrazol-3-yl) -6- (4-methylsulfonylpiperazin-1-yl) -2-styrylpyrimidin-4-amine Example 71 was synthesized as a suitable starting material. Synthesized according to Scheme 6 following the general scheme provided above, using nitronitrile, 5-methyl-1H-pyrazol-3-amine, and 4-methylsulfonylpiperazine. The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

(Example 76)

N- (5-Methyl-1H-pyrazol-3-yl) -6- (pyrrolidin-1-yl) -2-styrylpyrimidin-4-amine Example 76 is a suitable starting material, cinnamonitrile, 5 Synthesized according to Scheme 6 following the general scheme provided above using -methyl-1H-pyrazol-3-amine and pyrrolidine. The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

(Example 77)

The (2- (4-methylpiperazin-1-yl) ethyl) -2-styryl 4,6-diamine Example 77 - N ⁴ - (5- methyl -1H- pyrazole-3 ^-yl) -N 6 The general provided above using cinnamonitrile, 5-methyl-1H-pyrazol-3-amine, and 2- (4′-methylpiperazin-1′-yl) -aminoethane, suitable starting materials Synthesized according to Scheme 6 following the general scheme. The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

(Example 82)

N ⁴ - (5-methyl -1H- pyrazole-3 -yl) -N ⁶ - phenyl-2-styryl 4,6-diamine Example 82, an appropriate starting material cinnamonitrile, 5-methyl Synthesized according to Scheme 6 following the general scheme provided above using -1H-pyrazol-3-amine and aniline. The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

(Example 83)

N- (5-Methyl-1H-pyrazol-3-yl) -2-styryl-6-thiomorpholinopyrimidin-4-amine Example 83 was prepared from the appropriate starting material cinnamonitrile, 5-methyl-1H- Synthesized according to Scheme 6 following the general scheme provided above using pyrazol-3-amine and thiomorpholine. The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

(Example 86)

N ⁴ - (4-fluorophenyl) ^-N 6 - (5-methyl -1H- pyrazole-3 -yl) -2-styryl 4,6-diamine Example 86, an appropriate starting material Shin'namo Synthesized according to Scheme 6 following the general scheme provided above using nitrile, 5-methyl-1H-pyrazol-3-amine, and 4-fluoroaniline. The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

(Example 87)

(5-methyl -1H- pyrazole-3 -yl) -2-styryl 4,6-diamine Example ^{87, - N 4 - (2-} ( dimethylamino) ethyl) -N ⁴ - methyl ^-N 6 The general provided above using the appropriate starting materials cinnamonitrile, 5-methyl-1H-pyrazol-3-amine, and N ¹ , N ¹ , N ² -trimethylethane-1,2-diamine Synthesized according to Scheme 6 following the general scheme. The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

Example 99

N ⁴ - (tetrahydro -2H- pyran-4-yl) ^-N 6 - (5-methyl -1H- pyrazole-3 -yl) -2-styryl 4,6-diamine Example 99, the appropriate starting Synthesized according to Scheme 6 according to the general scheme provided above, using the materials cinnamonitrile, 5-methyl-1H-pyrazol-3-amine, and tetrahydro-2H-pyran-4-amine. The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

(Example 101)

1- (6- (5-Methyl-1H-pyrazol-3-ylamino) -2-styrylpyrimidin-4-yl) piperidin-4-ol Example 101 was prepared as an appropriate starting material, cinnamonitrile, 5- Synthesized according to Scheme 6 following the general scheme provided above, using methyl-1H-pyrazol-3-amine, and O-protected piperidin-4-ol. The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

(Example 103)

2- (4-Bromostyryl) -N- (5-methyl-1H-pyrazol-3-yl) -6- (4-methylpiperazin-1-yl) pyrimidin-4-amine Example 103 was prepared as a suitable starting material. Synthesized according to Scheme 6 according to the general scheme provided above, using the materials 3- (4-bromophenyl) -acrylonitrile, 5-methyl-1H-pyrazol-3-amine, and 4-methylpiperidine. . The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

(Example 160)

2- (4-Methoxystyryl) -N- (5-methyl-1H-pyrazol-3-yl) -6- (4-methylpiperazin-1-yl) pyrimidin-4-amine Example 160 is a suitable starting material. Synthesized according to Scheme 6 following the general scheme provided above, using the materials 3- (4-methoxyphenyl) -acrylonitrile, 5-methyl-1H-pyrazol-3-amine, and 4-methylpiperidine. . The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

(Example 161)

2- (4-Methoxystyryl) -N- (5-methyl-1H-pyrazol-3-yl) -6- (4-methylpiperazin-1-yl) pyrimidin-4-amine Example 161 was prepared as a suitable starting material. Synthesized according to Scheme 6 following the general scheme provided above, using the materials 3- (4-methoxyphenyl) -acrylonitrile, 5-methyl-1H-pyrazol-3-amine, and 4-methylpiperidine. . The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

(Example 162)

N ⁴ -((Furan-2-yl) methyl) -N ^6- (5-methyl-1H-pyrazol-3-yl) -2-styrylpyrimidine-4,6-diamine Example 162 was prepared as a suitable starting material. Scheme 6 according to the general scheme provided above with 3- (4-methoxyphenyl) -acrylonitrile, 5-methyl-1H-pyrazol-3-amine, and (furan-2-yl) methanamine Was synthesized. The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

(Example 163)

N ⁴ - (2-methoxyethyl) ^-N 6 - (5-methyl -1H- pyrazole-3 -yl) -2-styryl 4,6-diamine Example 163, a suitable starting material, thin Synthesized according to Scheme 6 following the general scheme provided above, using namonitrile, 5-methyl-1H-pyrazol-3-amine, and 2-methoxyethanamine. The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

(Example 164)

N ⁴ -((Tetrahydrofuran-2-yl) methyl) -N ^6- (5-methyl-1H-pyrazol-3-yl) -2-styrylpyrimidine-4,6-diamine Example 164 was prepared as appropriate starting material Was synthesized according to Scheme 6 according to the general scheme provided above using cinnamonitrile, 5-methyl-1H-pyrazol-3-amine, and (tetrahydrofuran-2-yl) methanamine. The desired structure was confirmed by ¹ H-NMR. ¹ H-NMR was attached.

( Biological experiment)
( Biological Experiment Example 1)
Aurora A (Aurora 2) Inhibition Assay Compounds were synthesized using the PanVera Z′-Lyte Kinase Assay Kit-Ser / Thr 1 peptide (Invitrogen, Carlsbad, Calif.) With their Aurora A (Upstate, Lake Placid, NY) Tested for effectiveness. The assay was performed in kinase assay buffer (50 mM HEPES, pH 7.5, 10 mM MgCl2, 5 mM EGTA, 0.05% Brij-35, ₂ mM DTT). Test compounds were first dissolved in DMSO at the highest test concentration of 100 × and then serially diluted to a 4 × test concentration in kinase assay buffer. Aurora A (final concentration 200-500 ng / mL), Z′-Lyte Ser / Thr 1 peptide (final concentration 2 μM) and ATP (final concentration 10 μM) were then added according to the manufacturer's instructions. The assay was performed in a half area 96 well white polystyrene assay plate (Corning, Corning, NY) with a final volume of 20 μl. The reaction was allowed to proceed for 1 hour in the dark at room temperature, at which point developing and stopping reagents were added according to the manufacturer's instructions. The fluorescence values of coumarin (Ex. 400 nm, Em. 465 nm) and fluorescein (Ex. 400 nm, Em. 565 nm) were measured with a SpectraFluor Plus plate reader (Tecan, Durham, NC). The luminescence ratio (coumarin / fluorescein) was determined and used to calculate the percentage of phosphorylation in each well. Wells with substrate but no kinase and wells with phosphopeptide controls were used to set 0% and 100% phosphorylation values, respectively. Generally 20-40% of the substrate was phosphorylated in wells without inhibitor. Dose response curves of specific Aurora A activity versus inhibitor concentration were plotted using Grafit (Erithacus Software, Horley, Surrey, UK).

Table 2 shows representative data for the inhibition of Aurora A by the compounds of the invention at a concentration of 100 μM.

( Biological Experiment Example 2)
Aurora B (Aurora 1) Inhibition Assay Aurora B kinase inhibition assay was performed similarly to Aurora A kinase (see above) with the following modifications. Aurora B kinase (BPS Biosciences, San Diego, Calif.) Was used as an enzyme at a concentration of 2.5 μg / mL. The ATP concentration was 50 μM and the kinase reaction was allowed to proceed for 16 hours. Sodium orthovanadate (20 μM) was added to the buffer to inhibit phosphatase contamination. Table 3 shows the data for inhibition of Aurora B by the compounds of the present invention at a concentration of 100 μM.

( Biological Experiment Example 3)
Ab1 Kinase Inhibition Assay Compounds were tested for Ab1 kinase inhibitory activity using N-terminal His _6- labeled recombinant human Ab1, residue 27 end (Upstate USA Inc, 706 Forest Street, Charlottesville, Virginia). Serial dilutions of the compounds were prepared as described above for Ab1 kinase (5-10 mU), 8 mM MOPS (3- (N-morpholino) propanesulfonic acid) pH 7.0, 0.2 mM EDTA (ethylenediaminetetraacetic acid), 50 μM amino acid sequence EAIYAAPFAKKKK ( A final reaction of 25 μL by incubating a solution of Upstate USA Inc., Charlottesville, Virginia, and 10 mM magnesium acetate and [γ- ³³ P-ATP] (specific activity of about 500 cpm / pmol, concentrated if necessary) Tested in volume. The reaction was initiated by the addition of magnesium acetate and [γ- ³³ P-ATP] mixture. After 40 minutes incubation at room temperature, the reaction was stopped by the addition of 5 μL of 3% phosphoric acid solution. A 10 μL aliquot of this reaction was then spotted onto a P30 filter mat (PerkinElmer, Wellesley, Mass.), Washed 3 times for 5 minutes in 75 mM phosphoric acid, washed once in methanol, then dried and scintillation counted. went. Inhibition of Ab1 activity was determined by comparison with an assay containing no inhibitor. Under these conditions, Example 31 produced about 77% inhibition of Ab1 at a concentration of 1 μM.

( Biological Experiment Example 4)
cKit Kinase Inhibition Assay Compounds were tested for cKit kinase inhibitory activity using N-terminal GST-labeled recombinant human cKit, residue 544-terminus (Upstate USA Inc, 706 Forest Street, Charlottesville, Virginia). Serial dilutions of compounds, the cKit kinase (5~10mU), 8mM MOPS (3- (N- morpholino) propanesulfonic acid) pH 7.0, 0.2 mM EDTA (ethylenediaminetetraacetic acid), 10 mM MnCl _2, 0.1 mg 25 μL of the final reaction by incubating a solution of 1 / mL polyglutamate-tyrosine 4: 1 and 10 mM magnesium acetate and [γ- ³³ P-ATP] (specific activity of about 500 cpm / pmol, concentrated if necessary) Tested by volume. The reaction was initiated by the addition of magnesium acetate and [γ- ³³ P-ATP] mixture. After 40 minutes incubation at room temperature, the reaction was stopped by the addition of 5 μL of 3% phosphoric acid solution. A 10 μL aliquot of this reaction was then spotted onto filter mat A, washed 3 times for 5 minutes in 75 mM phosphoric acid, washed once in methanol, then dried and subjected to scintillation counting. Inhibition of cKit activity was determined by comparison with an assay containing no inhibitor. Under these conditions, Example 31 produced about 86% inhibition of cKit at a concentration of 1 μM.

( Biological Experiment Example 5)
Src Kinase Inhibitory Activity Compounds were tested for Src kinase inhibitory activity using N-terminal His-labeled human Src (Upstate USA Inc, 706 Forest Street, Charlottesville, Virginia). Serial dilutions of the compounds were made using the Src kinase (5-10 mU), 8 mM MOPS (3- (N-morpholino) propanesulfonic acid) pH 7.0, 0.2 mM EDTA (ethylenediaminetetraacetic acid), 250 μM amino acid sequence KVEKIGEEGTYGVVYK (Upstate USA). By incubating a solution of Inc, 706 Forest Street, Charlottesville, Virginia, and 10 mM magnesium acetate and [γ- ³³ P-ATP] (specific activity of about 500 cpm / pmol, optionally concentrated) The reaction volume was tested. The reaction was initiated by the addition of magnesium acetate and [γ- ³³ P-ATP] mixture. After 40 minutes incubation at room temperature, the reaction was stopped by the addition of 5 μL of 3% phosphoric acid solution. A 10 μL aliquot of this reaction was then spotted onto a P30 filter mat (PerkinElmer, Wellesley, Mass.), Washed 3 times for 5 minutes in 75 mM phosphoric acid, washed once in methanol, then dried and scintillation counted. went. Inhibition of Src activity was determined by comparison with an assay containing no inhibitor. Under these conditions, Example 31 produced about 95% inhibition of Src at a concentration of 1 μM.

( Biological Experiment Example 6)
Flt3 Kinase Inhibitory Activity Compounds were tested for Flt3 kinase inhibitory activity using N-terminal GST-labeled recombinant human Flt3, residue 564-terminus (Upstate USA Inc, 706 Forest Street, Charlottesville, Virginia). Serial dilutions of the compounds were performed using the above Flt3 kinase (5-10 mU), 8 mM MOPS (3- (N-morpholino) propanesulfonic acid) pH 7.0, 0.2 mM EDTA (ethylenediaminetetraacetic acid), 50 μM amino acid sequence EAIYAAPFAKKKK (Upstate USA). By incubating a solution of Inc, 706 Forest Street, Charlottesville, Virginia, and 10 mM magnesium acetate and [γ- ³³ P-ATP] (specific activity of about 500 cpm / pmol, optionally concentrated) The reaction volume was tested. The reaction was initiated by the addition of magnesium acetate and [γ- ³³ P-ATP] mixture. After 40 minutes incubation at room temperature, the reaction was stopped by the addition of 5 μL of 3% phosphoric acid solution. A 10 μL aliquot of this reaction was then spotted onto a P30 filter mat (PerkinElmer, Wellesley, Mass.), Washed 3 times for 5 minutes in 75 mM phosphoric acid, washed once in methanol, then dried and scintillation counted. went. Inhibition of Flt3 activity was determined by comparison with an assay containing no inhibitor. Under these conditions, Example 31 produced about 96% inhibition of Flt3 at a concentration of 1 μM.

( Biological Experiment Example 7)
KDR Kinase Inhibitory Activity Compounds were tested for KDR kinase inhibitory activity using N-terminal His _6- labeled recombinant human KDR, residue 790-end (Upstate USA Inc, 706 Forest Street, Charlottesville, Virginia). Serial dilutions of compounds were made using the above KDR kinase (5-10 mU), 8 mM MOPS (3- (N-morpholino) propanesulfonic acid) pH 7.0, 0.2 mM EDTA (ethylenediaminetetraacetic acid), 0.33 mg / mL myelin base. Incubating a solution of sex protein (Upstate USA Inc, 706 Forest Street, Charlottesville, Virginia) and 10 mM magnesium acetate and [γ- ³³ P-ATP] (specific activity of about 500 cpm / pmol, concentrated if necessary) Were tested in a final reaction volume of 25 μL. The reaction was initiated by the addition of magnesium acetate and [γ- ³³ P-ATP] mixture. After 40 minutes incubation at room temperature, the reaction was stopped by the addition of 5 μL of 3% phosphoric acid solution. A 10 μL aliquot of this reaction was then spotted onto a P30 filter mat (PerkinElmer, Wellesley, Mass.), Washed 3 times for 5 minutes in 75 mM phosphoric acid, washed once in methanol, then dried and scintillation counted. went. Inhibition of KDR activity was determined by comparison with an assay containing no inhibitor. Under these conditions, Example 31 produced about 94% inhibition of KDR at a concentration of 1 μM.

( Biological Experiment Example 8)
Lck Kinase Inhibitory Activity Compounds were tested for Lck kinase inhibitory activity using recombinant full length human N-terminal His-tagged Lck, residue 790-end (Upstate USA Inc, 706 Forest Street, Charlottesville, Virginia). Serial dilutions of compounds were made using the above Lck kinase (5-10 mU), 50 mM Tris-pH 7.0, 0.1 mM EGTA (ethylene glycol bis [2-aminoethyl ether] tetraacetic acid), 0.1 mM Na ₃ VO ₄ , 0 0.1% β-mercaptoethanol, 0.1 mg / mL polyglutamate-tyrosine 4: 1, and 10 mM magnesium acetate and [γ- ³³ P-ATP] (specific activity of about 500 cpm / pmol, concentrated if necessary) Were tested in a final reaction volume of 25 μL. The reaction was initiated by the addition of magnesium acetate and [γ- ³³ P-ATP] mixture. After 40 minutes incubation at room temperature, the reaction was stopped by the addition of 5 μL of 3% phosphoric acid solution. A 10 μL aliquot of this reaction was then spotted onto filter mat A, washed 3 times for 5 minutes in 75 mM phosphoric acid, washed once in methanol, then dried and subjected to scintillation counting. Inhibition of Lck activity was determined by comparison with an assay containing no inhibitor. Under these conditions, Example 31 produced about 98% inhibition of Lck at a concentration of 1 μM.

( Biological Experiment Example 9)
Kinase selectivity assay Compounds were tested for inhibitory activity against a group of different kinase enzymes at a concentration of 1 μM. Where necessary, full-length enzymes or catalytically active fragments with N-terminal or C-terminal His or GST tags were used (Invitrogen, Carlsbad, CA). Test compounds were first diluted to 100 × test concentration in 100% DMSO. This 100 × concentration was then diluted to 4 × working concentration in kinase buffer (50 mM HEPES pH 7.5, 0.01% Brij-35, 10 mM MgCl ₂ , 1 mM EGTA) and 2.5 μL was then added to low volume NBS. , 384 well plate (Corning, Coming, NY). Then, if necessary (described in Table 3), 5 μL of 2 × peptide / kinase mixture (Invitrogen, Carlsbad, Calif.) Was added, after which the reaction was 2.5 μL of 4 × working concentration in kinase buffer. Started by addition of ATP. Inhibition values were determined at an ATP concentration equal to the apparent K _m for each individual kinase, or at an ATP concentration of 100 μM if the apparent K _m could not be achieved. Table 4 shows the percentage inhibition obtained in Example 10 and Example 31 under these conditions.

( Biological Experiment Example 10)
Total cytotoxicity assay: sulforhodamine B
Reference: Developmental Therapeutics Program NCI / NIH
http: // dtp. nci. nih. gov / branches / btb / ivclsp. html
Distributing the human tumor-derived cell line, HCT116 or MCF7 (ATCC), to a 96-well plate of DMEM containing 10% fetal calf serum and 2 mM L-glutamine at a density of 500 HCT116 cells or 1,000 MCF7 cells per well; After incubation for 24 hours at 37 ° C., 5% CO ₂ , experimental compounds were added. Compounds were added to the replicate plates using the indicated dilution series and the cells were incubated for 96 hours in medium plus compound. Additional plates were fixed in 10% TCA at the time of compound addition and the cell population at time zero, the time of drug addition, was measured. Following the 96 hour incubation, the medium was gently aspirated, and then the cells were fixed in place by adding 50 ul of ice-cold 10% TCA per well and incubating at 4 ° C. for 60 minutes. The plate was washed 5 times with tap water and allowed to air dry for 5 minutes. 50ul of 0.4% (weight / volume) sulforhodamine B solution in 1% (volume / volume) acetic acid was added per well and the cells were incubated at room temperature for 30 minutes. Following staining, the plates were washed 4 times with 1% acetic acid to remove unbound dye and then air dried for 5 minutes. The dye was solubilized with 100 ul of 10 mM Tris pH 10.5 per well and placed on an orbital rotator for 5 minutes. Absorbance was measured at 570 nm. Percent growth was determined using the following formula: Plate at time 0 (Tz) and dilution series plate (C) containing column of cells cultured in medium without compound as control (C) Calculated using absorbance measurements from
[(Ti−Tz) / (C−Tz)] × 100 at a concentration of Ti> / = Tz.
[(Ti−Tz) / Tz] × 100 at a concentration where Ti <Tz.

  Three dose response parameters were calculated for each experimental drug. 50% growth inhibition (GI50) was calculated from [(Ti−Tz) / (C−Tz)] × 100 = 50, which is a 50% decrease in net protein increase in control cells during drug incubation (SRB). The drug concentration yielding (measured by staining). The drug concentration resulting in total growth inhibition (TGI) was calculated from Ti = Tz. LC50 showing the net loss of cells after treatment (concentration of drug resulting in a 50% reduction in the last measured protein compared to the beginning of drug treatment) from [(Ti−Tz) / Tz] × 100 = −50 Calculated. Numerical values were calculated for each of these three parameters when the level of activity was achieved. However, if the effect was not achieved or was excessive, the numerical value of the parameter is expressed as greater or less than the maximum or minimum test concentration.

Table 5 shows representative values for inhibition of HCT-116 cell proliferation by the compounds of the present invention at a concentration of 100 μM.

Claims (15)

The following formula

And a compound selected from the biologically acceptable salts thereof, wherein:
R ^x and R ^y are independently selected from the group consisting of —T—R ³ and —L—Z—R ³ ;
Q ′ is −CR ^{6 ″} = CR ^{6 ″} − and

Wherein -CR ^{6 "} = CR ^6" -may be a cis or trans double bond or a mixture thereof;
R ¹ is -T-ring D;
Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from the group consisting of aryl, heteroaryl, heterocyclyl, and carbocyclyl, and the heteroaryl or heterocyclyl ring includes nitrogen, oxygen, and having from 1 to 4 ring heteroatoms selected from the group consisting of sulfur, wherein each substitutable ring carbon of ring D is oxo, -T-R 5 or ^-V-Z-, Independently substituted by R ⁵ and each substitutable ring nitrogen of ring D is independently substituted by —R ⁴ ;
T is a valence bond;
Z is a C _1-4 alkylidene chain;
L _{is, -O -, - S -,} - SO -, - SO 2 -, - N (R 6) SO 2 -, - SO 2 N (R 6) -, - N (R 6) -, - CO _{^{-, - CO 2 -, -}} N (R 6) CO -, - N (R 6) C (O) O -, - N (R 6) CON (R 6) -, - N (R 6) SO 2 N (R ⁶ ) —, —N (R ⁶ ) N (R ⁶ ) —, —C (O) N (R ⁶ ) —, —OC (O) N (R ⁶ ) —, —C (R ⁶ ) _{^{2 O -, - C (R}} 6) 2 -, - C (R 6) 2 SO -, - C (R 6) 2 SO 2 -, - C (R 6) 2 SO 2 N (R 6) -, _{^{-C (R 6) 2 N (}} R 6) -, - C (R 6) 2 N (R 6) C (O) -, - C (R 6) 2 N (R 6) C (O) O- ^{, -C (R 6) = NN} (R 6) -, - C (R 6) = N-O -, - C (R 6) 2 N (R 6 ) N (R ⁶ ) —, —C (R ⁶ ) ₂ N (R ⁶ ) SO ₂ N (R ⁶ ) —, and —C (R ⁶ ) ₂ N (R ⁶ ) CON (R ⁶ ) —. Selected from the group;
R ² and R ^{2 ′} are independently selected from the group consisting of —R and —T—W—R ⁶ , or R ² and R ^{2 ′} together with the atoms between them, nitrogen, oxygen And forms a fused 5-8 membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from the group consisting of, and sulfur, wherein R ² and R ^{2 ′} form Each substituted ring carbon of said fused ring is independently substituted by halo, oxo, —CN, —NO ₂ , R ⁷ , or —V—R ⁶ , and is substituted by R ² and R ^{2 ′} Each substitutable ring nitrogen of said ring formed is independently substituted by -R ⁴ ;
R ³ is —R, —halo, —OR, —C (═O) R, —CO ₂ R, —COCOR, —COCH ₂ COR, —NO ₂ , —CN, —S (O) R, —S. (O) ₂ R, —SR, —N (R ⁴ ) ₂ , —CON (R ⁷ ) ₂ , —SO ₂ N (R ⁷ ) ₂ , —OC (═O) R, —N (R ⁷ ) COR , —N (R ⁷ ) CO ₂ ( linear, branched, or cyclic C _1-6 alkyl, alkenyl, and alkynyl groups ), —N (R ⁴ ) N (R ⁴ ) ₂ , — _{^{C = NN (R 4) 2}} , -C = N-OR, -N (R 7) CON (R 7) 2, -N (R 7) SO 2 N (R 7) 2, -N (R 4) Selected from the group consisting of SO ₂ R, and —OC (═O) N (R) ₂ ;
Each R is independently hydrogen, or a linear, branched, or cyclic C _1-6 alkyl, alkenyl, and alkynyl group , C _6-10 aryl, 5-10 It is a heteroaryl ring, and optionally substituted group selected from the group consisting of a heterocyclyl ring having 5-10 ring atoms having a ring atom;
Each R ⁴ represents —R ⁷ , —COR ⁷ , —CO ₂ (optionally substituted linear, branched, or cyclic C _1-6 alkyl, alkenyl, and alkynyl groups ), — CON (R ⁷ ) ₂ as well as independently selected from the group consisting of —SO ₂ R ⁷ ;
Each R ⁵ is —R, halo, —OR, —C (═O) R, —CO ₂ R, —COCOR, —NO ₂ , —CN, —S (O) R, —SO ₂ R, — SR, —N (R ⁴ ) ₂ , —CON (R ⁴ ) ₂ , —SO ₂ N (R ⁴ ) ₂ , —OC (═O) R, —N (R ⁴ ) COR, —N (R ⁴ ) CO ₂ (optionally substituted straight chain, branched, or cyclic C _{1 to 6} alkyl, alkenyl, and alkynyl ^{groups), - N (R 4)} N (R 4) 2, -C = NN (R ⁴ ) ₂ , —C═N—OR, —N (R ⁴ ) CON (R ⁴ ) ₂ , —N (R ⁴ ) SO ₂ N (R ⁴ ) ₂ , —N (R ⁴ ) SO ₂ Independently selected from the group consisting of R, as well as —OC (═O) N (R ⁴ ) ₂ ;
V _{is, -O -, - S -,} - SO -, - SO 2 -, - N (R 6) SO 2 -, - SO 2 N (R 6) -, - N (R 6) -, - CO _{^{-, - CO 2 -, -}} N (R 6) CO -, - N (R 6) C (O) O -, - N (R 6) CON (R 6) -, - N (R 6) SO 2 N (R ⁶ ) —, —N (R ⁶ ) N (R ⁶ ) —, —C (O) N (R ⁶ ) —, —OC (O) N (R ⁶ ) —, —C (R ⁶ ) ₂ O—, —C (R ⁶ ) ₂ S—, —C (R ⁶ ) ₂ SO—, —C (R ⁶ ) ₂ SO ₂ —, —C (R ⁶ ) ₂ SO ₂ N (R ⁶ ) — _{^{, -C (R 6) 2 N}} (R 6), - C (R 6) 2 N (R 6) C (O) -, - C (R 6) 2 N (R 6) C (O) O- ^{, -C (R 6) = NN} (R 6) -, - C (R 6) = N-O -, - C (R 6) 2 N (R 6 ) N (R ⁶ ) —, —C (R ⁶ ) ₂ N (R ⁶ ) SO ₂ N (R ⁶ ) —, and —C (R ⁶ ) ₂ N (R ⁶ ) CON (R ⁶ ) —. Selected from the group;
W represents —C (R ⁶ ) ₂ O—, —C (R ⁶ ) ₂ S—, —C (R ⁶ ) ₂ SO—, —C (R ⁶ ) ₂ SO ₂ —, —C (R ⁶ ). _{^{2 SO 2 N (R 6)}} -, - C (R 6) 2 N (R 6) -, - CO -, - CO 2 -, - C (R 6) OC (O) -, - C (R 6 _{^{) OC (O) N (R}} 6) -, - C (R 6) 2 N (R 6) CO -, - C (R 6) 2 N (R 6) C (O) O -, - C (R ⁶ ) = NN (R ⁶ )-, -C (R ⁶ ) = N-O-, -C (R ⁶ ) ₂ N (R ⁶ ) N (R ⁶ )-, -C (R ⁶ ) ₂ N ( Selected from the group consisting of R ⁶ ) SO ₂ N (R ⁶ ) —, —C (R ⁶ ) ₂ N (R ⁶ ) CON (R ⁶ ) —, and —CON (R ⁶ ) —;
Each R ⁶ is independently selected from the group consisting of hydrogen and optionally substituted linear, branched, or cyclic C _1-4 alkyl, alkenyl, and alkynyl groups , or the same nitrogen Two R ⁶ groups on the atom can be taken together with the nitrogen atom to form a 3-6 membered heterocyclyl or heteroaryl ring;
Each R ^{6 ″} is hydrogen, linear, branched, or cyclic C _1-4 alkyl, alkenyl, and alkynyl groups , halogen, optionally substituted aryl, and optionally substituted hetero Independently selected from the group consisting of aryl;
Each R ⁷ is independently selected from the group consisting of hydrogen and optionally substituted linear, branched, or cyclic C _1-6 alkyl, alkenyl, and alkynyl groups , or the same nitrogen The top two R ⁷ together with the nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring.
A compound selected from the following group or a biologically acceptable salt thereof.

The following formula

Or a biologically acceptable salt thereof.   4. A compound according to claim 2 or 3 incorporated into particles having an average particle size of less than 2 microns.   4. A compound according to claim 2 or 3 incorporated into a biodegradable or non-biodegradable polymer. A pharmaceutical composition comprising a compound selected from the compounds according to claim 2 or 3 and an additive. The additives include antioxidants, buffers, bacteriostatic agents, liquid carriers, solutes, suspending agents, thickening agents, flavoring agents, gelatin, glycerin, binders, lubricants, inert diluents, storage 7. The pharmaceutical composition according to claim 6, selected from agents, surfactants, dispersants, biodegradable polymers, or any combination thereof. The pharmaceutical composition according to claim 6 or 7, for treating cancer. The cancer is solid tumor, hematogenous tumor, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular tumor, urogenital tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, Skin cancer, keratinous squamous cell carcinoma, lung cancer, squamous cell carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone tumor, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular adenocarcinoma, undifferentiated Cancer, papillary tumor, seminoma, melanoma, sarcoma, bladder cancer, liver and bile duct cancer, kidney cancer, bone marrow disorder, lymphatic disorder, Hodgkin's disease, hairy cell leukemia, buccal cavity cancer, pharyngeal cancer 9. A pharmaceutical composition according to claim 8, wherein the composition is lip cancer, tongue cancer, mouth cancer, small intestine cancer, colorectal cancer, colon cancer, rectal cancer, brain tumor and central nervous system cancer, or leukemia. The method according to claim 6 or 7, for inhibiting a kinase selected from the group consisting of Aurora A protein kinase, Aurora B protein kinase, Ab1 kinase, cKit kinase, Src kinase, Flt 3 kinase, KDR kinase, and Lck kinase. Pharmaceutical composition. The composition comprises tablets, capsules, lozenges, cachets, solutions, suspensions, emulsions, powders, aerosols, suppositories, sprays, pastilles, ointments, creams, pastes, foams, gels, tampons, The pharmaceutical composition according to any one of claims 6 to 10, which is in the form of a pessary, granule, bolus, mouthwash, or transdermal patch.   Use of a compound according to any one of claims 1 to 5 in the manufacture of a medicament for treating cancer. The cancer is solid tumor, hematogenous tumor, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular tumor, urogenital tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, Skin cancer, keratinous squamous cell carcinoma, lung cancer, squamous cell carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone tumor, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular adenocarcinoma, undifferentiated Cancer, papillary tumor, seminoma, melanoma, sarcoma, bladder cancer, liver and bile duct cancer, kidney cancer, bone marrow disorder, lymphatic disorder, Hodgkin's disease, hairy cell leukemia, buccal cavity cancer, pharyngeal cancer The use according to claim 12, which is lip cancer, tongue cancer, mouth cancer, small intestine cancer, colorectal cancer, colon cancer, rectal cancer, brain tumor and central nervous system cancer, or leukemia.   In the manufacture of a medicament for inhibiting a kinase selected from the group consisting of Aurora A protein kinase, Aurora B protein kinase, Ab1 kinase, cKit kinase, Src kinase, Flt 3 kinase, KDR kinase, and Lck kinase. Use of a compound according to any one of -5.   The drug is a tablet, capsule, lozenge, cachet, solution, suspension, emulsion, powder, aerosol, suppository, spray, pastille, ointment, cream, paste, foam, gel, tampon, pessary 15. Use according to any one of claims 12 to 14, in the form of a granule, bolus, mouthwash or transdermal patch.